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MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

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Abstract

Despite dopamine–glutamate aberrant interaction that has long been considered a relevant landmark of psychosis pathophysiology, several aspects of these two neurotransmitters reciprocal interaction remain to be defined. The emerging role of postsynaptic density (PSD) proteins at glutamate synapse as a molecular “lego” making a functional hub where different signals converge may add a new piece of information to understand how dopamine–glutamate interaction may work with regard to schizophrenia pathophysiology and treatment. More recently, compelling evidence suggests a relevant role for microRNA (miRNA) as a new class of dopamine and glutamate modulators with regulatory functions in the reciprocal interaction of these two neurotransmitters. Here, we aimed at addressing the following issues: (i) Do miRNAs have a role in schizophrenia pathophysiology in the context of dopamine–glutamate aberrant interaction? (ii) If miRNAs are relevant for dopamine–glutamate interaction, at what level this modulation takes place? (iii) Finally, will this knowledge open the door to innovative diagnostic and therapeutic tools? The biogenesis of miRNAs and their role in synaptic plasticity with relevance to schizophrenia will be considered in the context of dopamine–glutamate interaction, with special focus on miRNA interaction with PSD elements. From this framework, implications both for biomarkers identification and potential innovative interventions will be considered.

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References

  1. Horvath S, Mirnics K (2014) Schizophrenia as a disorder of molecular pathways. Biol Psychiatry. doi:10.1016/j.biopsych.2014.01.001

    PubMed Central  Google Scholar 

  2. de Bartolomeis A, Buonaguro EF, Iasevoli F (2013) Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins. Psychopharmacology (Berl) 225(1):1–19. doi:10.1007/s00213-012-2921-8

    Article  CAS  Google Scholar 

  3. Catts VS, Fung SJ, Long LE, Joshi D, Vercammen A, Allen KM, Fillman SG, Rothmond DA, Sinclair D, Tiwari Y, Tsai SY, Weickert TW, Shannon Weickert C (2013) Rethinking schizophrenia in the context of normal neurodevelopment. Front Cell Neurosci 7:60. doi:10.3389/fncel.2013.00060

    Article  PubMed  PubMed Central  Google Scholar 

  4. Alexander-Bloch AF, Reiss PT, Rapoport J, McAdams H, Giedd JN, Bullmore ET, Gogtay N (2014) Abnormal cortical growth in schizophrenia targets normative modules of synchronized development. Biol Psychiatry. doi:10.1016/j.biopsych.2014.02.010

    PubMed  PubMed Central  Google Scholar 

  5. Vargas G (2014) Biomarkers in schizophrenia. Biomark Med 8(1):1–3. doi:10.2217/bmm.13.138

    Article  CAS  PubMed  Google Scholar 

  6. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 94(6):2569–2574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Abi-Dargham A (2002) Recent evidence for dopamine abnormalities in schizophrenia. Eur Psychiatry 17(4):341s–347s

    Article  PubMed  Google Scholar 

  8. Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci 1003:138–158

    Article  CAS  PubMed  Google Scholar 

  9. Kraguljac NV, Reid MA, White DM, den Hollander J, Lahti AC (2012) Regional decoupling of N-acetyl-aspartate and glutamate in schizophrenia. Neuropsychopharmacology 37(12):2635–2642. doi:10.1038/npp.2012.126 npp2012126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kraguljac NV, White DM, Reid MA, Lahti AC (2013) Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia. JAMA Psychiatry 70(12):1294–1302. doi:10.1001/jamapsychiatry.2013.2437 1748839

    Article  CAS  PubMed  Google Scholar 

  11. Meisenzahl EM, Schmitt G, Grunder G, Dresel S, Frodl T, la Fougere C, Scheuerecker J, Schwarz M, Boerner R, Stauss J, Hahn K, Moller HJ (2008) Striatal D2/D3 receptor occupancy, clinical response and side effects with amisulpride: an iodine-123-iodobenzamide SPET study. Pharmacopsychiatry 41(5):169–175. doi:10.1055/s-2008-1076727

    Article  CAS  PubMed  Google Scholar 

  12. Elkis H (2007) Treatment-resistant schizophrenia. Psychiatr Clin North Am 30(3):511–533. doi:10.1016/j.psc.2007.04.001

    Article  PubMed  Google Scholar 

  13. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM (2007) MicroRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 8(2):R27. doi:10.1186/gb-2007-8-2-r27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Santarelli DM, Liu B, Duncan CE, Beveridge NJ, Tooney PA, Schofield PR, Cairns MJ (2013) Gene-microRNA interactions associated with antipsychotic mechanisms and the metabolic side effects of olanzapine. Psychopharmacology (Berl) 227(1):67–78. doi:10.1007/s00213-012-2939-y

    Article  CAS  Google Scholar 

  15. Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ (2010) Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15(12):1176–1189. doi:10.1038/mp.2009.84 mp200984

    Article  CAS  PubMed  Google Scholar 

  16. Kim AH, Reimers M, Maher B, Williamson V, McMichael O, McClay JL, van den Oord EJ, Riley BP, Kendler KS, Vladimirov VI (2010) MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 124(1–3):183–191. doi:10.1016/j.schres.2010.07.002 S0920-9964(10)01381-2

    Article  PubMed  PubMed Central  Google Scholar 

  17. Srinivasan S, Selvan ST, Archunan G, Gulyas B, Padmanabhan P (2013) MicroRNAs—the next generation therapeutic targets in human diseases. Theranostics 3(12):930–942. doi:10.7150/thno.7026 thnov03p0930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sekar TV, Mohanram RK, Foygel K, Paulmurugan R (2013) Therapeutic evaluation of microRNAs by molecular imaging. Theranostics 3(12):964–985. doi:10.7150/thno.4928 thnov03p0964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wibrand K, Panja D, Tiron A, Ofte ML, Skaftnesmo KO, Lee CS, Pena JT, Tuschl T, Bramham CR (2010) Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo. Eur J Neurosci 31(4):636–645. doi:10.1111/j.1460-9568.2010.07112.x

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lugli G, Torvik VI, Larson J, Smalheiser NR (2008) Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain. J Neurochem 106(2):650–661. doi:10.1111/j.1471-4159.2008.05413.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Paschou M, Paraskevopoulou MD, Vlachos IS, Koukouraki P, Hatzigeorgiou AG, Doxakis E (2012) miRNA regulons associated with synaptic function. PLoS One 7(10):e46189. doi:10.1371/journal.pone.0046189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20(5):515–524. doi:10.1101/gad.1399806

    Article  CAS  PubMed  Google Scholar 

  23. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956):415–419. doi:10.1038/nature01957

    Article  CAS  PubMed  Google Scholar 

  24. He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5(7):522–531. doi:10.1038/nrg1379

    Article  CAS  PubMed  Google Scholar 

  25. Yeom KH, Lee Y, Han J, Suh MR, Kim VN (2006) Characterization of DGCR8/Pasha, the essential cofactor for Drosha in primary miRNA processing. Nucleic Acids Res 34(16):4622–4629. doi:10.1093/nar/gkl458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee YS, Nakahara K, Pham JW, Kim K, He Z, Sontheimer EJ, Carthew RW (2004) Distinct roles for drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117(1):69–81

    Article  CAS  PubMed  Google Scholar 

  27. Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T (2004) Human Argonaute 2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell 15(2):185–197. doi:10.1016/j.molcel.2004.07.007

    Article  CAS  PubMed  Google Scholar 

  28. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9(2):102–114. doi:10.1038/nrg2290

    Article  CAS  PubMed  Google Scholar 

  29. Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W (2006) Stress-induced reversal of microRNA repression and mRNA P-body localization in human cells. Cold Spring Harb Symp Quant Biol 71:513–521. doi:10.1101/sqb.2006.71.038

    Article  CAS  PubMed  Google Scholar 

  30. Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318(5858):1931–1934. doi:10.1126/science.1149460

    Article  CAS  PubMed  Google Scholar 

  31. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5(3):R13. doi:10.1186/gb-2004-5-3-r13

    Article  PubMed  PubMed Central  Google Scholar 

  32. Boudreau RL, Jiang P, Gilmore BL, Spengler RM, Tirabassi R, Nelson JA, Ross CA, Xing Y, Davidson BL (2014) Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81(2):294–305. doi:10.1016/j.neuron.2013.10.062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheng LC, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12(4):399–408. doi:10.1038/nn.2294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Higa GS, de Sousa E, Walter LT, Kinjo ER, Resende RR, Kihara AH (2014) MicroRNAs in neuronal communication. Mol Neurobiol 49(3):1309–1326. doi:10.1007/s12035-013-8603-7

    CAS  PubMed  Google Scholar 

  35. Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M, Khudayberdiev S, Leuschner PF, Busch CJ, Kane C, Hubel K, Dekker F, Hedberg C, Rengarajan B, Drepper C, Waldmann H, Kauppinen S, Greenberg ME, Draguhn A, Rehmsmeier M, Martinez J, Schratt GM (2009) A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 11(6):705–716. doi:10.1038/ncb1876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21(7):744–749. doi:10.1101/gad.1519107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM, Ruvkun G (2004) Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc Natl Acad Sci U S A 101(1):360–365. doi:10.1073/pnas.2333854100

    Article  CAS  PubMed  Google Scholar 

  38. Krichevsky AM, Sonntag KC, Isacson O, Kosik KS (2006) Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 24(4):857–864. doi:10.1634/stemcells.2005-0441

    Article  CAS  PubMed  Google Scholar 

  39. Conaco C, Otto S, Han JJ, Mandel G (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 103(7):2422–2427. doi:10.1073/pnas.0511041103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cuellar TL, Davis TH, Nelson PT, Loeb GB, Harfe BD, Ullian E, McManus MT (2008) Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. Proc Natl Acad Sci U S A 105(14):5614–5619. doi:10.1073/pnas.0801689105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, Ullian EM (2008) Conditional loss of dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 28(17):4322–4330. doi:10.1523/JNEUROSCI.4815-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shin D, Shin JY, McManus MT, Ptacek LJ, Fu YH (2009) Dicer ablation in oligodendrocytes provokes neuronal impairment in mice. Ann Neurol 66(6):843–857. doi:10.1002/ana.21927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Konopka W, Kiryk A, Novak M, Herwerth M, Parkitna JR, Wawrzyniak M, Kowarsch A, Michaluk P, Dzwonek J, Arnsperger T, Wilczynski G, Merkenschlager M, Theis FJ, Kohr G, Kaczmarek L, Schutz G (2010) MicroRNA loss enhances learning and memory in mice. J Neurosci 30(44):14835–14842. doi:10.1523/JNEUROSCI.3030-10.2010

    Article  CAS  PubMed  Google Scholar 

  44. Tao J, Wu H, Lin Q, Wei W, Lu XH, Cantle JP, Ao Y, Olsen RW, Yang XW, Mody I, Sofroniew MV, Sun YE (2011) Deletion of astroglial Dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J Neurosci 31(22):8306–8319. doi:10.1523/JNEUROSCI.0567-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Barbee SA, Estes PS, Cziko AM, Hillebrand J, Luedeman RA, Coller JM, Johnson N, Howlett IC, Geng C, Ueda R, Brand AH, Newbury SF, Wilhelm JE, Levine RB, Nakamura A, Parker R, Ramaswami M (2006) Staufen- and FMRP-containing neuronal RNPs are structurally and functionally related to somatic P bodies. Neuron 52(6):997–1009. doi:10.1016/j.neuron.2006.10.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lugli G, Larson J, Martone ME, Jones Y, Smalheiser NR (2005) Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. J Neurochem 94(4):896–905. doi:10.1111/j.1471-4159.2005.03224.x

    Article  CAS  PubMed  Google Scholar 

  47. Wang DO, Kim SM, Zhao Y, Hwang H, Miura SK, Sossin WS, Martin KC (2009) Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324(5934):1536–1540. doi:10.1126/science.1173205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cao X, Yeo G, Muotri AR, Kuwabara T, Gage FH (2006) Noncoding RNAs in the mammalian central nervous system. Annu Rev Neurosci 29:77–103. doi:10.1146/annurev.neuro.29.051605.112839

    Article  CAS  PubMed  Google Scholar 

  49. Mehler MF, Mattick JS (2006) Non-coding RNAs in the nervous system. J Physiol 575(2):333–341. doi:10.1113/jphysiol.2006.113191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Abelson JF, Kwan KY, O'Roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M, Davis NR, Ercan-Sencicek AG, Guez DH, Spertus JA, Leckman JF, Dure LS, Kurlan R, Singer HS, Gilbert DL, Farhi A, Louvi A, Lifton RP, Sestan N, State MW (2005) Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 310(5746):317–320. doi:10.1126/science.1116502

    Article  CAS  PubMed  Google Scholar 

  51. Bagni C, Greenough WT (2005) From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci 6(5):376–387. doi:10.1038/nrn1667

    Article  CAS  PubMed  Google Scholar 

  52. Caudy AA, Myers M, Hannon GJ, Hammond SM (2002) Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev 16(19):2491–2496. doi:10.1101/gad.1025202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, Lao K, Kosik KS (2008) Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics 9(3):153–161. doi:10.1007/s10048-008-0133-5

    Article  CAS  PubMed  Google Scholar 

  54. Talebizadeh Z, Butler MG, Theodoro MF (2008) Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res 1(4):240–250. doi:10.1002/aur.33

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sarachana T, Zhou R, Chen G, Manji HK, Hu VW (2010) Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome Med 2(4):23. doi:10.1186/gm144 gm144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, Batterton MN, Tada T, Dolan BM, Sharp PA, Sheng M (2010) Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132. Neuron 65(3):373–384. doi:10.1016/j.neuron.2010.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Iasevoli F, Tomasetti C, de Bartolomeis A (2013) Scaffolding proteins of the post-synaptic density contribute to synaptic plasticity by regulating receptor localization and distribution: relevance for neuropsychiatric diseases. Neurochem Res 38(1):1–22. doi:10.1007/s11064-012-0886-y

    Article  CAS  PubMed  Google Scholar 

  58. de Bartolomeis A, Tomasetti C (2012) Calcium-dependent networks in dopamine–glutamate interaction: the role of postsynaptic scaffolding proteins. Mol Neurobiol 46(2):275–296. doi:10.1007/s12035-012-8293-6

    Article  CAS  PubMed  Google Scholar 

  59. de Bartolomeis A, Latte G, Tomasetti C, Iasevoli F (2013) Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches. Mol Neurobiol. doi:10.1007/s12035-013-8534-3

    PubMed  Google Scholar 

  60. Miller BH, Zeier Z, Xi L, Lanz TA, Deng S, Strathmann J, Willoughby D, Kenny PJ, Elsworth JD, Lawrence MS, Roth RH, Edbauer D, Kleiman RJ, Wahlestedt C (2012) MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc Natl Acad Sci U S A 109(8):3125–3130. doi:10.1073/pnas.1113793109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ, Tran N, Dedova I, Cairns MJ (2008) Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet 17(8):1156–1168. doi:10.1093/hmg/ddn005

    Article  CAS  PubMed  Google Scholar 

  62. Lindsay EA, Greenberg F, Shaffer LG, Shapira SK, Scambler PJ, Baldini A (1995) Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region. Am J Med Genet 56(2):191–197. doi:10.1002/ajmg.1320560216

    Article  CAS  PubMed  Google Scholar 

  63. Murphy KC, Jones LA, Owen MJ (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 56(10):940–945

    Article  CAS  PubMed  Google Scholar 

  64. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA (2008) Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 40(6):751–760. doi:10.1038/ng.138

    Article  CAS  PubMed  Google Scholar 

  65. Mukai J, Dhilla A, Drew LJ, Stark KL, Cao L, MacDermott AB, Karayiorgou M, Gogos JA (2008) Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci 11(11):1302–1310. doi:10.1038/nn.2204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA (2013) Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 152(1–2):262–275. doi:10.1016/j.cell.2012.11.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Earls LR, Bayazitov IT, Fricke RG, Berry RB, Illingworth E, Mittleman G, Zakharenko SS (2010) Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome. J Neurosci 30(47):15843–15855. doi:10.1523/JNEUROSCI.1425-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Earls LR, Fricke RG, Yu J, Berry RB, Baldwin LT, Zakharenko SS (2012) Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia. J Neurosci 32(41):14132–14144. doi:10.1523/JNEUROSCI.1312-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ (2011) Upregulation of Dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry 69(2):180–187. doi:10.1016/j.biopsych.2010.09.030

    Article  CAS  PubMed  Google Scholar 

  70. Moreau MP, Bruse SE, David-Rus R, Buyske S, Brzustowicz LM (2011) Altered microRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol Psychiatry 69(2):188–193. doi:10.1016/j.biopsych.2010.09.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Banigan MG, Kao PF, Kozubek JA, Winslow AR, Medina J, Costa J, Schmitt A, Schneider A, Cabral H, Cagsal-Getkin O, Vanderburg CR, Delalle I (2013) Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One 8(1):e48814. doi:10.1371/journal.pone.0048814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wong J, Duncan CE, Beveridge NJ, Webster MJ, Cairns MJ, Weickert CS (2013) Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia. Schizophr Bull 39(2):396–406. doi:10.1093/schbul/sbr177

    Article  PubMed  Google Scholar 

  73. Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40(7):880–885. doi:10.1038/ng.162

    Article  CAS  PubMed  Google Scholar 

  74. Zhu Y, Kalbfleisch T, Brennan MD, Li Y (2009) A microRNA gene is hosted in an intron of a schizophrenia-susceptibility gene. Schizophr Res 109(1–3):86–89. doi:10.1016/j.schres.2009.01.022

    Article  PubMed  PubMed Central  Google Scholar 

  75. Mellios N, Galdzicka M, Ginns E, Baker SP, Rogaev E, Xu J, Akbarian S (2012) Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia. Schizophr Bull 38(3):433–443. doi:10.1093/schbul/sbq091

    Article  PubMed  Google Scholar 

  76. Burmistrova OA, Goltsov AY, Abramova LI, Kaleda VG, Orlova VA, Rogaev EI (2007) MicroRNA in schizophrenia: genetic and expression analysis of miR-130b (22q11). Biochemistry (Mosc) 72(5):578–582

    Article  CAS  Google Scholar 

  77. Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E, Andreassen OA, Djurovic S, Melle I, Agartz I, Hall H, Timm S, Wang AG, Werge T (2007) Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One 2(9):e873. doi:10.1371/journal.pone.0000873

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Xu Y, Li F, Zhang B, Zhang K, Zhang F, Huang X, Sun N, Ren Y, Sui M, Liu P (2010) MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia. Schizophr Res 119(1–3):219–227. doi:10.1016/j.schres.2010.02.1070

    Article  PubMed  Google Scholar 

  79. Feng J, Sun G, Yan J, Noltner K, Li W, Buzin CH, Longmate J, Heston LL, Rossi J, Sommer SS (2009) Evidence for X-chromosomal schizophrenia associated with microRNA alterations. PLoS One 4(7):e6121. doi:10.1371/journal.pone.0006121

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Genome-wide association study identifies five new schizophrenia loci (2011) Nat Genet 43(10):969–976. doi:10.1038/ng.940

    Article  CAS  Google Scholar 

  81. Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, Teng ZQ, Luo Y, Peng J, Bordey A, Jin P, Zhao X (2010) MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28(6):1060–1070. doi:10.1002/stem.431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Guella I, Sequeira A, Rollins B, Morgan L, Torri F, van Erp TG, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, Akil H, Bunney WE, Potkin SG, Macciardi F, Vawter MP (2013) Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. J Psychiatr Res 47(9):1215–1221. doi:10.1016/j.jpsychires.2013.05.021

    Article  PubMed  PubMed Central  Google Scholar 

  83. Whalley HC, Papmeyer M, Romaniuk L, Sprooten E, Johnstone EC, Hall J, Lawrie SM, Evans KL, Blumberg HP, Sussmann JE, McIntosh AM (2012) Impact of a microRNA miR-137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder. Neuropsychopharmacology 37(12):2720–2729. doi:10.1038/npp.2012.137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lett TA, Chakavarty MM, Felsky D, Brandl EJ, Tiwari AK, Goncalves VF, Rajji TK, Daskalakis ZJ, Meltzer HY, Lieberman JA, Lerch JP, Mulsant BH, Kennedy JL, Voineskos AN (2013) The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia. Mol Psychiatry 18(4):443–450. doi:10.1038/mp.2013.17

    Article  CAS  PubMed  Google Scholar 

  85. Cummings E, Donohoe G, Hargreaves A, Moore S, Fahey C, Dinan TG, McDonald C, O'Callaghan E, O'Neill FA, Waddington JL, Murphy KC, Morris DW, Gill M, Corvin A (2013) Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at miR-137. Neurosci Lett 532:33–38. doi:10.1016/j.neulet.2012.08.065

    Article  CAS  PubMed  Google Scholar 

  86. Green MJ, Cairns MJ, Wu J, Dragovic M, Jablensky A, Tooney PA, Scott RJ, Carr VJ (2013) Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia. Mol Psychiatry 18(7):774–780. doi:10.1038/mp.2012.84

    Article  CAS  PubMed  Google Scholar 

  87. Zhou Y, Wang J, Lu X, Song X, Ye Y, Zhou J, Ying B, Wang L (2013) Evaluation of six SNPs of microRNA machinery genes and risk of schizophrenia. J Mol Neurosci 49(3):594–599. doi:10.1007/s12031-012-9887-1

    Article  CAS  PubMed  Google Scholar 

  88. Lai CY, Yu SL, Hsieh MH, Chen CH, Chen HY, Wen CC, Huang YH, Hsiao PC, Hsiao CK, Liu CM, Yang PC, Hwu HG, Chen WJ (2011) MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. PLoS One 6(6):e21635. doi:10.1371/journal.pone.0021635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA, Cairns MJ (2012) Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry 17(8):827–840. doi:10.1038/mp.2011.78

    Article  CAS  PubMed  Google Scholar 

  90. Shi W, Du J, Qi Y, Liang G, Wang T, Li S, Xie S, Zeshan B, Xiao Z (2012) Aberrant expression of serum miRNAs in schizophrenia. J Psychiatr Res 46(2):198–204. doi:10.1016/j.jpsychires.2011.09.010

    Article  PubMed  Google Scholar 

  91. Gallego JA, Gordon ML, Claycomb K, Bhatt M, Lencz T, Malhotra AK (2012) In vivo microRNA detection and quantitation in cerebrospinal fluid. J Mol Neurosci 47(2):243–248. doi:10.1007/s12031-012-9731-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192(4238):481–483

    Article  CAS  PubMed  Google Scholar 

  93. Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1(2):133–152. doi:10.1002/syn.890010203

    Article  CAS  PubMed  Google Scholar 

  94. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93(17):9235–9240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hietala J, Syvalahti E, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M, Solin O, Kuoppamaki M, Kirvela O, Ruotsalainen U et al (1995) Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346(8983):1130–1131

    Article  CAS  PubMed  Google Scholar 

  96. Lindstrom LH, Gefvert O, Hagberg G, Lundberg T, Bergstrom M, Hartvig P, Langstrom B (1999) Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by l-(beta-11C) DOPA and PET. Biol Psychiatry 46(5):681–688

    Article  CAS  PubMed  Google Scholar 

  97. Sawaguchi T, Goldman-Rakic PS (1994) The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 71(2):515–528

    CAS  PubMed  Google Scholar 

  98. Abi-Dargham A, Moore H (2003) Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist 9(5):404–416

    Article  CAS  PubMed  Google Scholar 

  99. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10(3):376–384. doi:10.1038/nn1846

    Article  CAS  PubMed  Google Scholar 

  100. Moghaddam B, Javitt D (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37(1):4–15. doi:10.1038/npp.2011.181

    Article  CAS  PubMed  Google Scholar 

  101. Iasevoli F, Tomasetti C, Buonaguro EF, de Bartolomeis A (2014) The glutamatergic aspects of schizophrenia molecular pathophysiology: role of the postsynaptic density, and implications for treatment. Curr Neuropharmacol 12(3):219–238. doi:10.2174/1570159X12666140324183406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17(3):141–150. doi:10.1016/S0893-133X(97)00036-5

    Article  CAS  PubMed  Google Scholar 

  103. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D (1997) Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 154(6):805–811

    Article  CAS  PubMed  Google Scholar 

  104. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA (1995) Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport 6(6):869–872

    Article  CAS  PubMed  Google Scholar 

  105. Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D'Souza DC (2005) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62(9):985–994. doi:10.1001/archpsyc.62.9.985

    Article  CAS  PubMed  Google Scholar 

  106. Reid MA, Kraguljac NV, Avsar KB, White DM, den Hollander JA, Lahti AC (2013) Proton magnetic resonance spectroscopy of the substantia nigra in schizophrenia. Schizophr Res 147(2–3):348–354. doi:10.1016/j.schres.2013.04.036

    Article  PubMed  PubMed Central  Google Scholar 

  107. Marquis JP, Audet MC, Dore FY, Goulet S (2007) Delayed alternation performance following subchronic phencyclidine administration in rats depends on task parameters. Prog Neuropsychopharmacol Biol Psychiatry 31(5):1108–1112. doi:10.1016/j.pnpbp.2007.03.017

    Article  CAS  PubMed  Google Scholar 

  108. Didriksen M, Skarsfeldt T, Arnt J (2007) Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics. Psychopharmacology (Berl) 193(2):225–233. doi:10.1007/s00213-007-0774-3

    Article  CAS  Google Scholar 

  109. Pedersen CS, Goetghebeur P, Dias R (2009) Chronic infusion of PCP via osmotic mini-pumps: a new rodent model of cognitive deficit in schizophrenia characterized by impaired attentional set-shifting (ID/ED) performance. J Neurosci Methods 185(1):66–69. doi:10.1016/j.jneumeth.2009.09.014

    Article  CAS  PubMed  Google Scholar 

  110. McKibben CE, Jenkins TA, Adams HN, Harte MK, Reynolds GP (2010) Effect of pretreatment with risperidone on phencyclidine-induced disruptions in object recognition memory and prefrontal cortex parvalbumin immunoreactivity in the rat. Behav Brain Res 208(1):132–136. doi:10.1016/j.bbr.2009.11.018

    Article  CAS  PubMed  Google Scholar 

  111. Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33(6):523–533

    Article  CAS  PubMed  Google Scholar 

  112. Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17(8):2921–2927

    CAS  PubMed  Google Scholar 

  113. Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117(3):697–706

    Article  CAS  PubMed  Google Scholar 

  114. Lopez-Gil X, Babot Z, Amargos-Bosch M, Sunol C, Artigas F, Adell A (2007) Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology 32(10):2087–2097. doi:10.1038/sj.npp.1301356

    Article  CAS  PubMed  Google Scholar 

  115. Jentsch JD, Elsworth JD, Redmond DE Jr, Roth RH (1997) Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: modulation by the isomers of HA966. J Neurosci 17(5):1769–1775

    CAS  PubMed  Google Scholar 

  116. Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF (2005) Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology 30(10):1861–1869. doi:10.1038/sj.npp.1300732

    Article  CAS  PubMed  Google Scholar 

  117. Jentsch JD, Wise A, Katz Z, Roth RH (1998) Alpha-noradrenergic receptor modulation of the phencyclidine- and delta9-tetrahydrocannabinol-induced increases in dopamine utilization in rat prefrontal cortex. Synapse 28(1):21–26. doi:10.1002/(SICI)1098-2396(199801)28

    Article  CAS  PubMed  Google Scholar 

  118. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22(9):3708–3719

    CAS  PubMed  Google Scholar 

  119. Ladepeche L, Yang L, Bouchet D, Groc L (2013) Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses. PLoS One 8(9):e74512. doi:10.1371/journal.pone.0074512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sarantis K, Matsokis N, Angelatou F (2009) Synergistic interactions of dopamine D1 and glutamate NMDA receptors in rat hippocampus and prefrontal cortex: involvement of ERK1/2 signaling. Neuroscience 163(4):1135–1145. doi:10.1016/j.neuroscience.2009.07.056

    Article  CAS  PubMed  Google Scholar 

  121. Dunah AW, Standaert DG (2001) Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J Neurosci 21(15):5546–5558

    CAS  PubMed  Google Scholar 

  122. Hallett PJ, Spoelgen R, Hyman BT, Standaert DG, Dunah AW (2006) Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J Neurosci 26(17):4690–4700. doi:10.1523/JNEUROSCI.0792-06.2006

    Article  CAS  PubMed  Google Scholar 

  123. Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63(1):182–217. doi:10.1124/pr.110.002642

    Article  CAS  PubMed  Google Scholar 

  124. Kruse MS, Premont J, Krebs MO, Jay TM (2009) Interaction of dopamine D1 with NMDA NR1 receptors in rat prefrontal cortex. Eur Neuropsychopharmacol 19(4):296–304. doi:10.1016/j.euroneuro.2008.12.006

    Article  CAS  PubMed  Google Scholar 

  125. Iasevoli F, Tomasetti C, Marmo F, Bravi D, Arnt J, de Bartolomeis A (2010) Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole. Psychopharmacology (Berl) 212(3):329–344. doi:10.1007/s00213-010-1954-0

    Article  CAS  Google Scholar 

  126. de Bartolomeis A, Marmo F, Buonaguro EF, Rossi R, Tomasetti C, Iasevoli F (2013) Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. Eur Neuropsychopharmacol 23(11):1516–1529. doi:10.1016/j.euroneuro.2012.11.014

    Article  PubMed  CAS  Google Scholar 

  127. Iasevoli F, Tomasetti C, Ambesi-Impiombato A, Muscettola G, de Bartolomeis A (2009) Dopamine receptor subtypes contribution to Homer1a induction: insights into antipsychotic molecular action. Prog Neuropsychopharmacol Biol Psychiatry 33(5):813–821. doi:10.1016/j.pnpbp.2009.02.009

    Article  CAS  PubMed  Google Scholar 

  128. Porras G, Berthet A, Dehay B, Li Q, Ladepeche L, Normand E, Dovero S, Martinez A, Doudnikoff E, Martin-Negrier ML, Chuan Q, Bloch B, Choquet D, Boue-Grabot E, Groc L, Bezard E (2012) PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking. J Clin Invest 122(11):3977–3989. doi:10.1172/JCI59426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ha CM, Park D, Han JK, Jang JI, Park JY, Hwang EM, Seok H, Chang S (2012) Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 protein and plays a role in dopamine receptor internalization. J Biol Chem 287(38):31813–31822. doi:10.1074/jbc.M112.370601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhang J, Xu TX, Hallett PJ, Watanabe M, Grant SG, Isacson O, Yao WD (2009) PSD-95 uncouples dopamine–glutamate interaction in the D1/PSD-95/NMDA receptor complex. J Neurosci 29(9):2948–2960. doi:10.1523/JNEUROSCI.4424-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. D'Aniello S, Somorjai I, Garcia-Fernandez J, Topo E, D'Aniello A (2011) d-aspartic acid is a novel endogenous neurotransmitter. FASEB J 25(3):1014–1027. doi:10.1096/fj.10-168492

    Article  PubMed  CAS  Google Scholar 

  132. Errico F, Napolitano F, Nistico R, Usiello A (2012) New insights on the role of free d-aspartate in the mammalian brain. Amino Acids 43(5):1861–1871. doi:10.1007/s00726-012-1356-1

    Article  CAS  PubMed  Google Scholar 

  133. Errico F, Napolitano F, Squillace M, Vitucci D, Blasi G, de Bartolomeis A, Bertolino A, D'Aniello A, Usiello A (2013) Decreased levels of d-aspartate and NMDA in the prefrontal cortex and striatum of patients with schizophrenia. J Psychiatr Res 47(10):1432–1437. doi:10.1016/j.jpsychires.2013.06.013

    Article  PubMed  Google Scholar 

  134. Errico F, Rossi S, Napolitano F, Catuogno V, Topo E, Fisone G, D'Aniello A, Centonze D, Usiello A (2008) d-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801. J Neurosci 28(41):10404–10414. doi:10.1523/JNEUROSCI.1618-08.2008

    Article  CAS  PubMed  Google Scholar 

  135. Sarantis K, Antoniou K, Matsokis N, Angelatou F (2012) Exposure to novel environment is characterized by an interaction of D1/NMDA receptors underlined by phosphorylation of the NMDA and AMPA receptor subunits and activation of ERK1/2 signaling, leading to epigenetic changes and gene expression in rat hippocampus. Neurochem Int 60(1):55–67. doi:10.1016/j.neuint.2011.10.018

    Article  CAS  PubMed  Google Scholar 

  136. Tobon KE, Chang D, Kuzhikandathil EV (2012) MicroRNA 142-3p mediates post-transcriptional regulation of D1 dopamine receptor expression. PLoS One 7(11):e49288. doi:10.1371/journal.pone.0049288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Huang W, Li MD (2009) Differential allelic expression of dopamine D1 receptor gene (DRD1) is modulated by microRNA miR-504. Biol Psychiatry 65(8):702–705. doi:10.1016/j.biopsych.2008.11.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX, Zhang GM, Feng ZH (2009) miR-142-3p restricts cAMP production in CD4+CD25- T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep 10(2):180–185. doi:10.1038/embor.2008.224

    Article  CAS  PubMed  Google Scholar 

  139. Fasano C, Bourque MJ, Lapointe G, Leo D, Thibault D, Haber M, Kortleven C, Desgroseillers L, Murai KK, Trudeau LE (2013) Dopamine facilitates dendritic spine formation by cultured striatal medium spiny neurons through both D1 and D2 dopamine receptors. Neuropharmacology 67:432–443. doi:10.1016/j.neuropharm.2012.11.030

    Article  CAS  PubMed  Google Scholar 

  140. Qi Z, Kikuchi S, Tretter F, Voit EO (2011) Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders. Pharmacopsychiatry 44(1):S62–75. doi:10.1055/s-0031-1273707

    Article  CAS  PubMed  Google Scholar 

  141. Scott L, Aperia A (2009) Interaction between N-methyl-d-aspartic acid receptors and D1 dopamine receptors: an important mechanism for brain plasticity. Neuroscience 158(1):62–66. doi:10.1016/j.neuroscience.2008.10.020

    Article  CAS  PubMed  Google Scholar 

  142. de Bartolomeis A, Fiore G (2004) Postsynaptic density scaffolding proteins at excitatory synapse and disorders of synaptic plasticity: implications for human behavior pathologies. Int Rev Neurobiol 59:221–254. doi:10.1016/S0074-7742(04)59009-8

    Article  PubMed  Google Scholar 

  143. Sheng M, Hoogenraad CC (2007) The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu Rev Biochem 76:823–847. doi:10.1146/annurev.biochem.76.060805.160029

    Article  CAS  PubMed  Google Scholar 

  144. Kneussel M (2005) Postsynaptic scaffold proteins at non-synaptic sites. The role of postsynaptic scaffold proteins in motor-protein-receptor complexes. EMBO Rep 6(1):22–27. doi:10.1038/sj.embor.7400319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5(10):771–781. doi:10.1038/nrn1517

    Article  CAS  PubMed  Google Scholar 

  146. Emes RD, Pocklington AJ, Anderson CN, Bayes A, Collins MO, Vickers CA, Croning MD, Malik BR, Choudhary JS, Armstrong JD, Grant SG (2008) Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat Neurosci 11(7):799–806. doi:10.1038/nn.2135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Anderson SM, Famous KR, Sadri-Vakili G, Kumaresan V, Schmidt HD, Bass CE, Terwilliger EF, Cha JH, Pierce RC (2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci 11(3):344–353. doi:10.1038/nn2054

    Article  CAS  PubMed  Google Scholar 

  148. Fernandez E, Schiappa R, Girault JA, Le Novere N (2006) DARPP-32 is a robust integrator of dopamine and glutamate signals. PLoS Comput Biol 2(12):e176. doi:10.1371/journal.pcbi.0020176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Mao LM, Zhang GC, Liu XY, Fibuch EE, Wang JQ (2008) Group I metabotropic glutamate receptor-mediated gene expression in striatal neurons. Neurochem Res 33(10):1920–1924. doi:10.1007/s11064-008-9654-4

    Article  CAS  PubMed  Google Scholar 

  150. Sutton LP, Rushlow WJ (2011) Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268. J Neurochem 117(6):973–983. doi:10.1111/j.1471-4159.2011.07268.x

    Article  CAS  PubMed  Google Scholar 

  151. Sutton LP, Rushlow WJ (2012) The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3. Int J Neuropsychopharmacol 15(7):965–979. doi:10.1017/S146114571100109X

    Article  CAS  PubMed  Google Scholar 

  152. Yang L, Mao L, Tang Q, Samdani S, Liu Z, Wang JQ (2004) A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. J Neurosci 24(48):10846–10857. doi:10.1523/JNEUROSCI.2496-04.2004

    Article  CAS  PubMed  Google Scholar 

  153. Beaulieu JM, Tirotta E, Sotnikova TD, Masri B, Salahpour A, Gainetdinov RR, Borrelli E, Caron MG (2007) Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci 27(4):881–885. doi:10.1523/JNEUROSCI.5074-06.2007

    Article  CAS  PubMed  Google Scholar 

  154. Clinton SM, Haroutunian V, Davis KL, Meador-Woodruff JH (2003) Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am J Psychiatry 160(6):1100–1109

    Article  PubMed  Google Scholar 

  155. Clinton SM, Meador-Woodruff JH (2004) Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology 29(7):1353–1362. doi:10.1038/sj.npp.1300451

    Article  CAS  PubMed  Google Scholar 

  156. Lugli G, Larson J, Demars MP, Smalheiser NR (2012) Primary microRNA precursor transcripts are localized at post-synaptic densities in adult mouse forebrain. J Neurochem 123(4):459–466. doi:10.1111/j.1471-4159.2012.07921.x

    Article  CAS  PubMed  Google Scholar 

  157. Kawashima H, Numakawa T, Kumamaru E, Adachi N, Mizuno H, Ninomiya M, Kunugi H, Hashido K (2010) Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression. Neuroscience 165(4):1301–1311. doi:10.1016/j.neuroscience.2009.11.057

    Article  CAS  PubMed  Google Scholar 

  158. Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, Sales N, Willoughby D, Elmen J, Hansen HF, Orum H, Kauppinen S, Kenny PJ, Wahlestedt C (2009) MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci U S A 106(9):3507–3512. doi:10.1073/pnas.0805854106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Liu X, Zhan Z, Xu L, Ma F, Li D, Guo Z, Li N, Cao X (2010) MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKIIalpha. J Immunol 185(12):7244–7251. doi:10.4049/jimmunol.1001573

    Article  CAS  PubMed  Google Scholar 

  160. Dutta R, Chomyk AM, Chang A, Ribaudo MV, Deckard SA, Doud MK, Edberg DD, Bai B, Li M, Baranzini SE, Fox RJ, Staugaitis SM, Macklin WB, Trapp BD (2013) Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol 73(5):637–645. doi:10.1002/ana.23860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Harraz MM, Eacker SM, Wang X, Dawson TM, Dawson VL (2012) MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc Natl Acad Sci U S A 109(46):18962–18967. doi:10.1073/pnas.1121288109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Wright C, Turner JA, Calhoun VD, Perrone-Bizzozero N (2013) Potential impact of miR-137 and its targets in schizophrenia. Front Genet 4:58. doi:10.3389/fgene.2013.00058

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, Impey S (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci U S A 105(26):9093–9098. doi:10.1073/pnas.0803072105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhang GC, Mao LM, Liu XY, Parelkar NK, Arora A, Yang L, Hains M, Fibuch EE, Wang JQ (2007) In vivo regulation of Homer1a expression in the striatum by cocaine. Mol Pharmacol 71(4):1148–1158. doi:10.1124/mol.106.028399

    Article  CAS  PubMed  Google Scholar 

  165. Tomasetti C, Dell'Aversano C, Iasevoli F, de Bartolomeis A (2007) Homer splice variants modulation within cortico-subcortical regions by dopamine D2 antagonists, a partial agonist, and an indirect agonist: implication for glutamatergic postsynaptic density in antipsychotics action. Neuroscience 150(1):144–158. doi:10.1016/j.neuroscience.2007.08.022

    Article  CAS  PubMed  Google Scholar 

  166. Ghasemzadeh MB, Windham LK, Lake RW, Acker CJ, Kalivas PW (2009) Cocaine activates Homer1 immediate early gene transcription in the mesocorticolimbic circuit: differential regulation by dopamine and glutamate signaling. Synapse 63(1):42–53. doi:10.1002/syn.20577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Saba R, Storchel PH, Aksoy-Aksel A, Kepura F, Lippi G, Plant TD, Schratt GM (2012) Dopamine-regulated microRNA miR-181a controls GluA2 surface expression in hippocampal neurons. Mol Cell Biol 32(3):619–632. doi:10.1128/MCB.05896-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chandrasekar V, Dreyer JL (2009) microRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity. Mol Cell Neurosci 42(4):350–362. doi:10.1016/j.mcn.2009.08.009

    Article  CAS  PubMed  Google Scholar 

  169. Delint-Ramirez I, Fernandez E, Bayes A, Kicsi E, Komiyama NH, Grant SG (2010) In vivo composition of NMDA receptor signaling complexes differs between membrane subdomains and is modulated by PSD-95 and PSD-93. J Neurosci 30(24):8162–8170. doi:10.1523/JNEUROSCI.1792-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Coba MP, Pocklington AJ, Collins MO, Kopanitsa MV, Uren RT, Swamy S, Croning MD, Choudhary JS, Grant SG (2009) Neurotransmitters drive combinatorial multistate postsynaptic density networks. Sci Signal 2(68):ra19. doi:10.1126/scisignal.2000102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Klugmann M, Szumlinski KK (2008) Targeting Homer genes using adeno-associated viral vector: lessons learned from behavioural and neurochemical studies. Behav Pharmacol 19(5–6):485–500. doi:10.1097/FBP.0b013e32830c369f

    Article  CAS  PubMed  Google Scholar 

  172. Ambesi-Impiombato A, Panariello F, Dell'aversano C, Tomasetti C, Muscettola G, de Bartolomeis A (2007) Differential expression of Homer 1 gene by acute and chronic administration of antipsychotics and dopamine transporter inhibitors in the rat forebrain. Synapse 61(6):429–439. doi:10.1002/syn.20385

    Article  CAS  PubMed  Google Scholar 

  173. Iasevoli F, Polese D, Ambesi-Impiombato A, Muscettola G, de Bartolomeis A (2007) Ketamine-related expression of glutamatergic postsynaptic density genes: possible implications in psychosis. Neurosci Lett 416(1):1–5. doi:10.1016/j.neulet.2007.01.041

    Article  CAS  PubMed  Google Scholar 

  174. de Bartolomeis A, Latte G, Tomasetti C, Iasevoli F (2014) Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches. Mol Neurobiol 49(1):484–511. doi:10.1007/s12035-013-8534-3

    Article  PubMed  CAS  Google Scholar 

  175. Boeckers TM (2006) The postsynaptic density. Cell Tissue Res 326(2):409–422. doi:10.1007/s00441-006-0274-5

    Article  CAS  PubMed  Google Scholar 

  176. Sun P, Wang J, Gu W, Cheng W, Jin GZ, Friedman E, Zheng J, Zhen X (2009) PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation. Cell Res 19(5):612–624. doi:10.1038/cr.2009.30

    Article  CAS  PubMed  Google Scholar 

  177. Clinton SM, Haroutunian V, Meador-Woodruff JH (2006) Up-regulation of NMDA receptor subunit and post-synaptic density protein expression in the thalamus of elderly patients with schizophrenia. J Neurochem 98(4):1114–1125. doi:10.1111/j.1471-4159.2006.03954.x

    Article  CAS  PubMed  Google Scholar 

  178. du Bois TM, Newell KA, Huang XF (2012) Perinatal phencyclidine treatment alters neuregulin 1/erbB4 expression and activation in later life. Eur Neuropsychopharmacol 22(5):356–363. doi:10.1016/j.euroneuro.2011.09.002

    Article  PubMed  CAS  Google Scholar 

  179. Feyder M, Karlsson RM, Mathur P, Lyman M, Bock R, Momenan R, Munasinghe J, Scattoni ML, Ihne J, Camp M, Graybeal C, Strathdee D, Begg A, Alvarez VA, Kirsch P, Rietschel M, Cichon S, Walter H, Meyer-Lindenberg A, Grant SG, Holmes A (2010) Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams syndrome. Am J Psychiatry 167(12):1508–1517. doi:10.1176/appi.ajp.2010.10040484

    Article  PubMed  PubMed Central  Google Scholar 

  180. Kristiansen LV, Beneyto M, Haroutunian V, Meador-Woodruff JH (2006) Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia. Mol Psychiatry 11(8):737–747. doi:10.1038/sj.mp.4001844

    Article  CAS  PubMed  Google Scholar 

  181. Park SW, Lee CH, Cho HY, Seo MK, Lee JG, Lee BJ, Seol W, Kee BS, Kim YH (2013) Effects of antipsychotic drugs on the expression of synaptic proteins and dendritic outgrowth in hippocampal neuronal cultures. Synapse 67(5):224–234. doi:10.1002/syn.21634

    Article  CAS  PubMed  Google Scholar 

  182. de Bartolomeis A, Sarappa C, Buonaguro EF, Marmo F, Eramo A, Tomasetti C, Iasevoli F (2013) Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. Prog Neuropsychopharmacol Biol Psychiatry 46:1–12. doi:10.1016/j.pnpbp.2013.06.010

    Article  PubMed  CAS  Google Scholar 

  183. Iasevoli F, Fiore G, Cicale M, Muscettola G, de Bartolomeis A (2010) Haloperidol induces higher Homer1a expression than risperidone, olanzapine and sulpiride in striatal sub-regions. Psychiatry Res 177(1–2):255–260. doi:10.1016/j.psychres.2010.02.009

    Article  CAS  PubMed  Google Scholar 

  184. Iasevoli F, Ambesi-Impiombato A, Fiore G, Panariello F, Muscettola G, de Bartolomeis A (2011) Pattern of acute induction of Homer1a gene is preserved after chronic treatment with first- and second-generation antipsychotics: effect of short-term drug discontinuation and comparison with Homer1a-interacting genes. J Psychopharmacol 25(7):875–887. doi:10.1177/0269881109358199

    Article  CAS  PubMed  Google Scholar 

  185. Muddashetty RS, Nalavadi VC, Gross C, Yao X, Xing L, Laur O, Warren ST, Bassell GJ (2011) Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol Cell 42(5):673–688. doi:10.1016/j.molcel.2011.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Cohen JE, Lee PR, Chen S, Li W, Fields RD (2011) MicroRNA regulation of homeostatic synaptic plasticity. Proc Natl Acad Sci U S A 108(28):11650–11655. doi:10.1073/pnas.1017576108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. de Bartolomeis A, Iasevoli F (2003) The Homer family and the signal transduction system at glutamatergic postsynaptic density: potential role in behavior and pharmacotherapy. Psychopharmacol Bull 37(3):51–83

    PubMed  Google Scholar 

  188. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23(3):583–592

    Article  CAS  PubMed  Google Scholar 

  189. Lominac KD, Oleson EB, Pava M, Klugmann M, Schwarz MK, Seeburg PH, During MJ, Worley PF, Kalivas PW, Szumlinski KK (2005) Distinct roles for different Homer1 isoforms in behaviors and associated prefrontal cortex function. J Neurosci 25(50):11586–11594. doi:10.1523/JNEUROSCI.3764-05.2005

    Article  CAS  PubMed  Google Scholar 

  190. Jaubert PJ, Golub MS, Lo YY, Germann SL, Dehoff MH, Worley PF, Kang SH, Schwarz MK, Seeburg PH, Berman RF (2007) Complex, multimodal behavioral profile of the Homer1 knockout mouse. Genes Brain Behav 6(2):141–154. doi:10.1111/j.1601-183X.2006.00240.x

    Article  CAS  PubMed  Google Scholar 

  191. Spellmann I, Rujescu D, Musil R, Mayr A, Giegling I, Genius J, Zill P, Dehning S, Opgen-Rhein M, Cerovecki A, Hartmann AM, Schafer M, Bondy B, Muller N, Moller HJ, Riedel M (2011) Homer-1 polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients. J Psychiatr Res 45(2):234–241. doi:10.1016/j.jpsychires.2010.06.004

    Article  PubMed  Google Scholar 

  192. Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC, Owen MJ (2003) Mutation screening of the Homer gene family and association analysis in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 120B(1):18–21. doi:10.1002/ajmg.b.20032

    Article  CAS  PubMed  Google Scholar 

  193. Yang L, Hong Q, Zhang M, Liu X, Pan XQ, Guo M, Fei L, Guo XR, Tong ML, Chi X (2013) The role of Homer 1a in increasing locomotor activity and non-selective attention, and impairing learning and memory abilities. Brain Res 1515:39–47. doi:10.1016/j.brainres.2013.03.030

    Article  CAS  PubMed  Google Scholar 

  194. Ghasemzadeh MB, Permenter LK, Lake RW, Kalivas PW (2003) Nucleus accumbens Homer proteins regulate behavioral sensitization to cocaine. Ann N Y Acad Sci 1003:395–397

    Article  PubMed  Google Scholar 

  195. Ghasemzadeh MB, Mueller C, Vasudevan P (2009) Behavioral sensitization to cocaine is associated with increased glutamate receptor trafficking to the postsynaptic density after extended withdrawal period. Neuroscience 159(1):414–426. doi:10.1016/j.neuroscience.2008.10.027

    Article  CAS  PubMed  Google Scholar 

  196. Reilly MT, Cunningham KA, Natarajan A (2009) Protein–protein interactions as therapeutic targets in neuropsychopharmacology. Neuropsychopharmacology 34(1):247–248. doi:10.1038/npp.2008.167

    Article  CAS  PubMed  Google Scholar 

  197. Molteni R, Calabrese F, Racagni G, Fumagalli F, Riva MA (2009) Antipsychotic drug actions on gene modulation and signaling mechanisms. Pharmacol Ther 124(1):74–85. doi:10.1016/j.pharmthera.2009.06.001

    Article  CAS  PubMed  Google Scholar 

  198. Olianas MC, Dedoni S, Onali P (2011) Regulation of PI3K/Akt signaling by N-desmethylclozapine through activation of delta-opioid receptor. Eur J Pharmacol 660(2–3):341–350. doi:10.1016/j.ejphar.2011.04.012

    Article  CAS  PubMed  Google Scholar 

  199. de Bartolomeis A, Sarappa C, Magara S, Iasevoli F (2012) Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol 682(1–3):1–11. doi:10.1016/j.ejphar.2012.02.033

    Article  PubMed  CAS  Google Scholar 

  200. Rizig MA, McQuillin A, Ng A, Robinson M, Harrison A, Zvelebil M, Hunt SP, Gurling HM (2012) A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia. J Psychopharmacol 26(9):1218–1230. doi:10.1177/0269881112450780

    Article  CAS  PubMed  Google Scholar 

  201. Weston-Green K, Huang XF, Deng C (2012) Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain. PLoS One 7(3):e33548. doi:10.1371/journal.pone.0033548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. de Bartolomeis A, Avvisati L, Iasevoli F, Tomasetti C (2013) Intracellular pathways of antipsychotic combined therapies: implication for psychiatric disorders treatment. Eur J Pharmacol 718(1–3):502–523. doi:10.1016/j.ejphar.2013.06.034

    Article  PubMed  CAS  Google Scholar 

  203. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA (2012) Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 17(12):1206–1227. doi:10.1038/mp.2012.47

    Article  CAS  PubMed  Google Scholar 

  204. Takebayashi H, Yamamoto N, Umino A, Nishikawa T (2014) Identification of developmentally regulated PCP-responsive non-coding RNA, prt6, in the rat thalamus. PLoS One 9(6):e97955. doi:10.1371/journal.pone.0097955

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Zhou R, Yuan P, Wang Y, Hunsberger JG, Elkahloun A, Wei Y, Damschroder-Williams P, Du J, Chen G, Manji HK (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34(6):1395–1405. doi:10.1038/npp.2008.131

    Article  CAS  PubMed  Google Scholar 

  206. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438(7068):685–689. doi:10.1038/nature04303

    Article  PubMed  CAS  Google Scholar 

  207. Brasnjevic I, Steinbusch HW, Schmitz C (2006) Altered gene expression and neuropathology in Alzheimer’s disease. Neurobiol Aging 27(8):1081–1083. doi:10.1016/j.neurobiolaging.2005.05.029

    Article  CAS  PubMed  Google Scholar 

  208. Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452(7189):896–899. doi:10.1038/nature06783

    Article  CAS  PubMed  Google Scholar 

  209. Kocerha J, Kauppinen S, Wahlestedt C (2009) MicroRNAs in CNS disorders. Neuromolecular Med 11(3):162–172. doi:10.1007/s12017-009-8066-1

    Article  CAS  PubMed  Google Scholar 

  210. Obad S, dos Santos CO, Petri A, Heidenblad M, Broom O, Ruse C, Fu C, Lindow M, Stenvang J, Straarup EM, Hansen HF, Koch T, Pappin D, Hannon GJ, Kauppinen S (2011) Silencing of microRNA families by seed-targeting tiny LNAs. Nat Genet 43(4):371–378. doi:10.1038/ng.786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. He Y, Yang C, Kirkmire CM, Wang ZJ (2010) Regulation of opioid tolerance by let-7 family microRNA targeting the mu opioid receptor. J Neurosci 30(30):10251–10258. doi:10.1523/JNEUROSCI.2419-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Hollander JA, Im HI, Amelio AL, Kocerha J, Bali P, Lu Q, Willoughby D, Wahlestedt C, Conkright MD, Kenny PJ (2010) Striatal microRNA controls cocaine intake through CREB signalling. Nature 466(7303):197–202. doi:10.1038/nature09202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Yen SK, Padmanabhan P, Selvan ST (2013) Multifunctional iron oxide nanoparticles for diagnostics, therapy and macromolecule delivery. Theranostics 3(12):986–1003. doi:10.7150/thno.4827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. do Hwang W, Son S, Jang J, Youn H, Lee S, Lee D, Lee YS, Jeong JM, Kim WJ, Lee DS (2011) A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA. Biomaterials 32(21):4968–4975. doi:10.1016/j.biomaterials.2011.03.047

    Article  CAS  PubMed  Google Scholar 

  215. Crew E, Tessel MA, Rahman S, Razzak-Jaffar A, Mott D, Kamundi M, Yu G, Tchah N, Lee J, Bellavia M, Zhong CJ (2012) MicroRNA conjugated gold nanoparticles and cell transfection. Anal Chem 84(1):26–29. doi:10.1021/ac202749p

    Article  CAS  PubMed  Google Scholar 

  216. Seto AG (2010) The road toward microRNA therapeutics. Int J Biochem Cell Biol 42(8):1298–1305. doi:10.1016/j.biocel.2010.03.003

    Article  CAS  PubMed  Google Scholar 

  217. Montgomery RL, van Rooij E (2011) Therapeutic advances in MicroRNA targeting. J Cardiovasc Pharmacol 57(1):1–7. doi:10.1097/FJC.0b013e3181f603d0

    Article  CAS  PubMed  Google Scholar 

  218. Cheng CJ, Saltzman WM (2012) Polymer nanoparticle-mediated delivery of microRNA inhibition and alternative splicing. Mol Pharm 9(5):1481–1488. doi:10.1021/mp300081s

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Shi SJ, Zhong ZR, Liu J, Zhang ZR, Sun X, Gong T (2012) Solid lipid nanoparticles loaded with anti-microRNA oligonucleotides (AMOs) for suppression of microRNA-21 functions in human lung cancer cells. Pharm Res 29(1):97–109. doi:10.1007/s11095-011-0514-6

    Article  CAS  PubMed  Google Scholar 

  220. Paulmurugan R (2013) MicroRNAs—a new generation molecular targets for treating cellular diseases. Theranostics 3(12):927–929. doi:10.7150/thno.8113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Novak J, Kruzliak P, Bienertova-Vasku J, Slaby O, Novak M (2014) MicroRNA-206: a promising theranostic marker. Theranostics 4(2):119–133. doi:10.7150/thno.7552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Henriksen M, Johnsen KB, Andersen HH, Pilgaard L, Duroux M (2014) MicroRNA expression signatures determine prognosis and survival in glioblastoma multiforme—a systematic overview. Mol Neurobiol. doi:10.1007/s12035-014-8668-y

    PubMed  PubMed Central  Google Scholar 

  223. Tufman A, Tian F, Huber RM (2013) Can microRNAs improve the management of lung cancer patients? A clinician’s perspective. Theranostics 3(12):953–963. doi:10.7150/thno.6615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Berger F, Reiser MF (2013) Micro-RNAs as potential new molecular biomarkers in oncology: have they reached relevance for the clinical imaging sciences? Theranostics 3(12):943–952. doi:10.7150/thno.7445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Tardito D, Mallei A, Popoli M (2013) Lost in translation. New unexplored avenues for neuropsychopharmacology: epigenetics and microRNAs. Expert Opin Investig Drugs 22(2):217–233. doi:10.1517/13543784.2013.749237

    Article  CAS  PubMed  Google Scholar 

  226. Maffioletti E, Tardito D, Gennarelli M, Bocchio-Chiavetto L (2014) Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders. Front Cell Neurosci 8:75. doi:10.3389/fncel.2014.00075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, Moran J, Chambert K, Toncheva D, Georgieva L, Grozeva D, Fjodorova M, Wollerton R, Rees E, Nikolov I, van de Lagemaat LN, Bayes A, Fernandez E, Olason PI, Bottcher Y, Komiyama NH, Collins MO, Choudhary J, Stefansson K, Stefansson H, Grant SG, Purcell S, Sklar P, O'Donovan MC, Owen MJ (2012) De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 17(2):142–153. doi:10.1038/mp.2011.154

    Article  CAS  PubMed  Google Scholar 

  228. Cheng MC, Lu CL, Luu SU, Tsai HM, Hsu SH, Chen TT, Chen CH (2010) Genetic and functional analysis of the DLG4 gene encoding the post-synaptic density protein 95 in schizophrenia. PLoS One 5(12):e15107. doi:10.1371/journal.pone.0015107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Hill MJ, Donocik JG, Nuamah RA, Mein CA, Sainz-Fuertes R, Bray NJ (2014) Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells. Schizophr Res 153(1–3):225–230. doi:10.1016/j.schres.2014.01.034

    Article  PubMed  PubMed Central  Google Scholar 

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de Bartolomeis, A., Iasevoli, F., Tomasetti, C. et al. MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective. Mol Neurobiol 52, 1771–1790 (2015). https://doi.org/10.1007/s12035-014-8962-8

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