, Volume 236, Issue 11, pp 3291–3300 | Cite as

Loss of dysbindin-1 affects GABAergic transmission in the PFC

  • H Trantham-Davidson
  • A LavinEmail author
Original Investigation


It has been shown that dystrobrevin-binding protein 1 gene that encodes the protein dysbindin-1 is associated with risk for cognitive deficits, and studies have shown decreases in glutamate and correlated decreases in dysbindin-1 protein in the prefrontal cortex (PFC) and hippocampus of post-mortem tissue from schizophrenia patients. The PFC and the hippocampus have been shown to play a fundamental role in cognition, and studies in dysbindin-1 null mice have shown alterations in NMDAR located in pyramidal neurons as well as perturbation in LTP and cognitive deficits. The balance between excitatory and inhibitory transmission is crucial for normal cognitive functions; however, there is a dearth of information regarding the effects of loss of dysbindin-1 in GABAergic transmission. Using in vitro whole-cell clamp recordings, Western blots, and immunohistochemistry, we report here that dysbindin-1-deficient mice exhibit a significant decrease in the frequency of sIPSCs and in the amplitude of mIPSCs and significant decreases in PV staining and protein level. These results suggest that loss of dysbindin-1 affects GABAergic transmission at pre- and postsynaptic level and decreases parvalbumin markers.


Dysbindin-1 Prefrontal cortex GABA Interneurons 


Compliance with ethical standards

All experimental protocols were approved by the Medical University of South Carolina Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Alherz F, Alherz M, Almusawi H (2017) NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: a newly identified correlation and its effects in schizophrenia. Schizophr Res Cogn 9(8):1–6Google Scholar
  2. Akbarian S, Huang HS (2006) Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev 52(2):293–304PubMedGoogle Scholar
  3. Baek JH, Kim JS, Ryu S, Oh S, Noh J, Lee WK, Park T, Lee YS, Lee D, Kwon JS, Hong KS (2012) Association of genetic variations in DTNBP1 with cognitive function in schizophrenia patients and healthy subjects. Am J Med Genet B Neuropsychiatr Genet 159B(7):841–849PubMedGoogle Scholar
  4. Bast T, Pezze M, McGarrity S (2017) Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition. Br J Pharmacol 174(19):3211–3225PubMedPubMedCentralGoogle Scholar
  5. Burdick KE, Goldberg TE, Funke B, Bates JA, Lencz T, Kucherlapati R, Malhotra AK (2007) DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 89(1–3):169–172PubMedGoogle Scholar
  6. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ (2007) Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 12(1):74–86PubMedGoogle Scholar
  7. Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41:237–260PubMedGoogle Scholar
  8. Carr GV, Jenkins KA, Weinberger DR, Papaleo F (2013) Loss of dysbindin-1 in mice impairs reward-based operant learning by increasing impulsive and compulsive behavior. Behav Brain Res 15(241):173–184Google Scholar
  9. Chen XW, Feng YQ, Hao CJ, Guo XL, He X, Zhou ZY, Guo N, Huang HP, Xiong W, Zheng H, Zuo PL, Zhang CX, Li W, Zhou Z (2008) DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. J Cell Biol 181(5):791–801PubMedPubMedCentralGoogle Scholar
  10. Chiba S, Hashimoto R, Hattori S, Yohda M, Lipska B, Weinberger DR, Kunugi H (2006) Effect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus. J Neural Transm 113(9):1337–1346PubMedGoogle Scholar
  11. Coyle JT (2017) Schizophrenia: basic and clinical. Adv Neurobiol 15:255–280PubMedGoogle Scholar
  12. Cox MM, Tucker AM, Tang J, Talbot K, Richer DC, Yeh L, Arnold SE (2009) Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background. Genes Brain Behav 8(4):390–397PubMedPubMedCentralGoogle Scholar
  13. Dienel SJ, Lewis DA (2018) Alterations in cortical interneurons and cognitive function in schizophrenia. Neurobiol Dis 22:S0969–9961(18)30199–2Google Scholar
  14. Dickman DK, Davis GW (2009) The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science. 326(5956):1127–1130PubMedPubMedCentralGoogle Scholar
  15. Dickman DK, Tong A, Davis GW (2012) Snapin is critical for presynaptic homeostatic plasticity. J Neurosci 32(25):8716–8724PubMedPubMedCentralGoogle Scholar
  16. Ferando I, Mody I (2015) In vitro gamma oscillations following partial and complete ablation of δ subunit-containing GABAA receptors from parvalbumin interneurons. Neuropharmacology. 88:91–98PubMedGoogle Scholar
  17. Ghiani CA, Starcevic M, Rodriguez-Fernandez IA, Nazarian R, Cheli VT, Chan LN, Malvar JS, de Vellis J, Sabatti C, Dell'Angelica EC (2010) The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth. Mol Psychiatry 15(2):115, 204–115, 215Google Scholar
  18. Ghiani CA, Dell'Angelica EC (2011) Dysbindin-containing complexes and their proposed functions in brain: from zero to (too) many in a decade. ASN Neuro. 27;3(2)Google Scholar
  19. Grace AA (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17(8):524–532PubMedPubMedCentralGoogle Scholar
  20. Glen WB Jr, Horowitz B, Carlson GC, Cannon TD, Talbot K, Jentsch JD, Lavin A (2014) Impaired hippocampal synaptic plasticity and contextual fear conditioning in dysbindin deficient mice. Hippocampus. 24(2):204–213. CrossRefPubMedGoogle Scholar
  21. Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V (2015) Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet 24(19):5512–5523PubMedPubMedCentralGoogle Scholar
  22. Gokhale A, Hartwig C, Freeman AH, Das R, Zlatic SA, Vistein R, Burch A, Carrot G, Lewis AF, Nelms S, Dickman DK, Puthenveedu MA, Cox DN, Faundez V (2016) The proteome of BLOC-1 genetic defects identifies the Arp2/3 actin polymerization complex to function downstream of the schizophrenia susceptibility factor dysbindin at the synapse. J Neurosci 36(49):12393–12411PubMedPubMedCentralGoogle Scholar
  23. Gonzalez-Burgos G, Lewis DA (2008) GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34(5):944–961PubMedPubMedCentralGoogle Scholar
  24. Gonzalez-Burgos G, Fish KN, Lewis DA (2011) GABA neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia. Neural Plast 2011:723184Google Scholar
  25. Guo JY, Ragland JD, Carter CS (2019) Memory and cognition in schizophrenia. Mol Psychiatry 24(5):633–642PubMedGoogle Scholar
  26. Hashimoto T, Arion D, Unger T, Maldonado-Avilés JG, Morris HM, Volk DW, Mirnics (2008) Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 13(2):147–161PubMedGoogle Scholar
  27. Hiser J, Koenigs M (2018) The multifaceted role of the ventromedial prefrontal cortex in emotion, decision making, social cognition, and psychopathology. Biol Psychiatry 83(8):638–647PubMedGoogle Scholar
  28. Huang Y, Yoon K, Ko H, Jiao S, Ito W, Wu JY, Yung WH, Lu B, Morozov A (2016) 5-HT3a receptors modulate hippocampal gamma oscillations by regulating synchrony of parvalbumin-positive interneurons. Cereb Cortex 26(2):576–585PubMedGoogle Scholar
  29. Huang CCY, Muszynski KJ, Bolshakov VY, Balu DT (2019) Deletion of Dtnbp1 in mice impairs threat memory consolidation and is associated with enhanced inhibitory drive in the amygdala. Transl Psychiatry 9(1):132PubMedPubMedCentralGoogle Scholar
  30. Ishikawa M, Mizukami K, Iwakiri M, Hidaka S, Asada T (2004) GABAA receptor gamma subunits in the prefrontal cortex of patients with schizophrenia and bipolar disorder. Neuroreport 15(11):1809–1812PubMedGoogle Scholar
  31. Jentsch JD, Trantham-Davidson H, Jairl C, Tinsley M, Cannon TD, Lavin A (2009) Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology. 34(12):2601–2608PubMedPubMedCentralGoogle Scholar
  32. Jia JM, Hu Z, Nordman J, Li Z (2014) The schizophrenia susceptibility gene dysbindin regulates dendritic spine dynamics. J Neurosci 34(41):13725–13736PubMedPubMedCentralGoogle Scholar
  33. Ji YF, Papaleo F, Wang HX, Gao WJ, Weinberger DR, Lu B (2009) Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci U S A 106(46):19593–19598PubMedPubMedCentralGoogle Scholar
  34. Karlsgodt KH, Robleto K, Trantham-Davidson H, Jairl C, Cannon TD, Lavin A, Jentsch JD (2011) Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry 69(1):28–34PubMedGoogle Scholar
  35. Kawaguchi Y, Kubota Y (1997) GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb Cortex 7(6):476–486PubMedGoogle Scholar
  36. Kumamoto N, Matsuzaki S, Inoue K, Hattori T, Shimizu S, Hashimoto R, Yamatodani A, Katayama T, Tohyama M (2006) Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin. Biochem Biophys Res Commun 345(2):904–909PubMedGoogle Scholar
  37. Larimore J, Tornieri K, Ryder PV, Gokhale A, Zlatic SA, Craige B, Lee JD, Talbot K, Pare JF, Smith Y, Faundez V (2011) The schizophrenia susceptibility factor dysbindin and its associated complex sort cargoes from cell bodies to the synapse. Mol Biol Cell 22(24):4854–4867PubMedPubMedCentralGoogle Scholar
  38. Larimore J, Zlatic SA, Arnold M, Singleton KS, Cross R, Rudolph H, Bruegge MV, Sweetman A, Garza C, Whisnant E, Faundez V (2017) Dysbindin deficiency modifies the expression of GABA neuron and ion permeation transcripts in the developing hippocampus. Front Genet 8:28PubMedPubMedCentralGoogle Scholar
  39. Lasztóczi B, Klausberger T (2014) Layer-specific GABAergic control of distinct gamma oscillations in the CA1 hippocampus. Neuron. 81(5):1126–1139PubMedGoogle Scholar
  40. Lee KH, Williams LM, Haig A, Gordon E (2003) “Gamma (40 Hz) phase synchronicity” and symptom dimensions in schizophrenia. Cogn Neuropsychiatry 8(1):57–71PubMedGoogle Scholar
  41. Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6(4):312–324PubMedGoogle Scholar
  42. Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63(10):1372–1376PubMedGoogle Scholar
  43. Lewis DA, Curley AA, Glausier JR, Volk DW (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 35(1):57–67PubMedGoogle Scholar
  44. Lewis DA (2014) Inhibitory neurons in human cortical circuits: substrate for cognitive dysfunction in schizophrenia. Curr Opin Neurobiol 26:22–26PubMedGoogle Scholar
  45. Lozano-Soldevilla D, ter Huurne N, Cools R, Jensen O (2014) GABAergic modulation of visual gamma and alpha oscillations and its consequences for working memory performance. Curr Biol 24(24):2878–2887PubMedGoogle Scholar
  46. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C (2004) Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 5(10):793–807PubMedGoogle Scholar
  47. Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P (2000) Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron. 28(1):53–67PubMedGoogle Scholar
  48. Mullin AP, Gokhale A, Larimore J, Faundez V (2011) Cell biology of the BLOC-1 complex subunit dysbindin, a schizophrenia susceptibility gene. Mol Neurobiol 44(1):53–64PubMedPubMedCentralGoogle Scholar
  49. Mullin AP, Sadanandappa MK, Ma W, Dickman DK, VijayRaghavan K, Ramaswami M, Sanyal S, Faundez V (2015) Gene dosage in the dysbindin schizophrenia susceptibility network differentially affect synaptic function and plasticity. J Neurosci 35(19):7643–7653PubMedPubMedCentralGoogle Scholar
  50. Newell-Litwa K, Salazar G, Smith Y, Faundez V (2009) Roles of BLOC-1 and adaptor protein-3 complexes in cargo sorting to synaptic vesicles. Mol Biol Cell 20(5):1441–1453PubMedPubMedCentralGoogle Scholar
  51. Newell-Litwa K, Chintala S, Jenkins S, Pare JF, McGaha L, Smith Y, Faundez V (2010) Hermansky-Pudlak protein complexes, AP-3 and BLOC-1, differentially regulate presynaptic composition in the striatum and hippocampus. J Neurosci 30(3):820–831PubMedPubMedCentralGoogle Scholar
  52. Papaleo F, Weinberger DR (2011) Dysbindin and schizophrenia: it's dopamine and glutamate all over again. Biol Psychiatry 69(1):2–4PubMedPubMedCentralGoogle Scholar
  53. Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN, Weinberger DR (2012) Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 17(1):85–98PubMedGoogle Scholar
  54. Papaleo F, Burdick MC, Callicott JH, Weinberger DR (2014) Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans. Mol Psychiatry 19(3):311–316PubMedGoogle Scholar
  55. Rao SG, Williams GV, Goldman-Rakic PS (2000) Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory. J Neurosci 20(1):485–494PubMedPubMedCentralGoogle Scholar
  56. Saggu S, Cannon TD, Jentsch JD, Lavin A (2013) Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice. Schizophr Res 146(1–3):254–263PubMedPubMedCentralGoogle Scholar
  57. Seamans JK, Nogueira L, Lavin A (2003) Synaptic basis of persistent activity in prefrontal cortex in vivo and in organotypic cultures. Cereb Cortex 13(11):1242–1250PubMedPubMedCentralGoogle Scholar
  58. Scheggia D, Mastrogiacomo R, Mereu M, Sannino S, Straub RE, Armando M, Managò F, Guadagna S, Piras F, Zhang F, Kleinman JE, Hyde TM, Kaalund SS, Pontillo M, Orso G, Caltagirone C, Borrelli E, De Luca MA, Vicari S, Weinberger DR, Spalletta G, Papaleo F, Publisher Correction (2018) Variations in dysbindin-1 are associated with cognitive response to antipsychotic drug treatment. Nat Commun 9(1):3560PubMedPubMedCentralGoogle Scholar
  59. Spencer KM, Nestor PG, Niznikiewicz MA, Salisbury DF, Shenton ME, McCarley RW (2003) Abnormal neural synchrony in schizophrenia. J Neurosci 23(19):7407–7411PubMedPubMedCentralGoogle Scholar
  60. Starcevic M, Dell'Angelica EC (2004) Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J Biol Chem 279(27):28393–28401PubMedGoogle Scholar
  61. Steullet P, Cabungcal JH, Coyle J, Didriksen M, Gill K, Grace AA, Hensch TK, LaMantia AS, Lindemann L, Maynard TM, Meyer U, Morishita H, O'Donnell P, Puhl M, Cuenod M, Do KQ (2017) Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry 22(7):936–943PubMedPubMedCentralGoogle Scholar
  62. Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, Hahn CG, Siegel SJ, Trojanowski JQ, Gur RE, Blake DJ, Arnold SE (2004) Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 113:1353–1363PubMedPubMedCentralGoogle Scholar
  63. Tang J, LeGros RP, Louneva N, Yeh L, Cohen JW, Hahn CG et al (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum Mol Genet 18:3851–3863PubMedPubMedCentralGoogle Scholar
  64. Toker L, Mancarci BO, Tripathy S, Pavlidis P (2018) Transcriptomic evidence for alterations in astrocytes and parvalbumin interneurons in subjects with bipolar disorder and schizophrenia. Biol Psychiatry 84(11):787–796PubMedGoogle Scholar
  65. Varela-Gomez N, Mata I, Perez-Iglesias R, Rodriguez-Sanchez JM, Ayesa R, Fatjo-Vilas M, Crespo-Facorro B (2015) Dysbindin gene variability is associated with cognitive abnormalities in first-episode non-affective psychosis. Cogn Neuropsychiatry 20(2):144–156PubMedGoogle Scholar
  66. Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM et al (2004) Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 61:544–555PubMedGoogle Scholar
  67. Weickert CS, Rothmond DA, Hyde TM, Kleinman JE, Straub RE (2008) Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res 98:105–110PubMedGoogle Scholar
  68. Winterer G, Weinberger DR (2004) Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 27(11):683–690PubMedGoogle Scholar
  69. Wirth C, Schubert F, Lautenschlager M, Brühl R, Klär A, Majic T, Lang UE, Ehrlich A, Winterer G, Sander T, Schouler-Ocak M, Gallinat J (2012) DTNBP1 (dysbindin) gene variants: in vivo evidence for effects on hippocampal glutamate status. Curr Pharm Biotechnol 13(8):1513–1521PubMedGoogle Scholar
  70. Whittington MA, Traub RD (2003) Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26(12):676–682PubMedGoogle Scholar
  71. Wolf C, Jackson MC, Kissling C, Thome J, Linden DE (2011) Dysbindin-1 genotype effects on emotional working memory. Mol Psychiatry 16(2):145–155PubMedGoogle Scholar
  72. Womelsdorf T, Schoffelen JM, Oostenveld R, Singer W, Desimone R, Engel AK, Fries P (2007) Modulation of neuronal interactions through neuronal synchronization. Science 316(5831):1609–1612PubMedGoogle Scholar
  73. Woo TU, Whitehead RE, Melchitzky DS, Lewis DA (1998) A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci U S A 95(9):5341–5346PubMedPubMedCentralGoogle Scholar
  74. Yuan Q, Yang F, Xiao Y, Tan S, Husain N, Ren M, Hu Z, Martinowich K, Ng JS, Kim PJ, Han W, Nagata KI, Weinberger DR, Je HS (2016) Regulation of brain-derived neurotrophic factor exocytosis and gamma-aminobutyric acidergic interneuron synapse by the schizophrenia susceptibility gene dysbindin-1. Biol Psychiatry 80(4):312–322PubMedGoogle Scholar
  75. Zhang ZJ, Reynolds GP (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55(1-2):1–10PubMedGoogle Scholar
  76. Zhang JP, Burdick KE, Lencz T, Malhotra AK (2010) Meta-analysis of genetic variation in DTNBP1 and general cognitive ability. Biol Psychiatry 68(12):1126–1133PubMedPubMedCentralGoogle Scholar
  77. Zinkstok JR, de Wilde O, van Amelsvoort TA, Tanck MW, Baas F, Linszen DH (2007) Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings. Behav Brain Funct 3:19PubMedPubMedCentralGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeuroscienceMUSCCharlestonUSA

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