Neurogranin Expression Is Regulated by Synaptic Activity and Promotes Synaptogenesis in Cultured Hippocampal Neurons

  • Alberto Garrido-García
  • Raquel de Andrés
  • Amanda Jiménez-Pompa
  • Patricia Soriano
  • Diego Sanz-Fuentes
  • Elena Martínez-Blanco
  • F. Javier Díez-GuerraEmail author


Neurogranin (Ng) is a calmodulin (CaM)-binding protein that is phosphorylated by protein kinase C (PKC) and is highly enriched in the dendrites and spines of telencephalic neurons. It is proposed to be involved in regulating CaM availability in the post-synaptic environment to modulate the efficiency of excitatory synaptic transmission. There is a close relationship between Ng and cognitive performance; its expression peaks in the forebrain coinciding with maximum synaptogenic activity, and it is reduced in several conditions of impaired cognition. We studied the expression of Ng in cultured hippocampal neurons and found that both protein and mRNA levels were about 10% of that found in the adult hippocampus. Long-term blockade of NMDA receptors substantially decreased Ng expression. On the other hand, treatments that enhanced synaptic activity such as long-term bicuculline treatment or co-culture with glial cells or cholesterol increased Ng expression. Chemical long-term potentiation (cLTP) induced an initial drop of Ng, with a minimum after 15 min followed by a slow recovery during the next 2–4 h. This effect was most evident in the synaptosome-enriched fraction, thus suggesting local synthesis in dendrites. Lentiviral expression of Ng led to increased density of both excitatory and inhibitory synapses in the second and third weeks of culture. These results indicate that Ng expression is regulated by synaptic activity and that Ng promotes the synaptogenesis process. Given its relationship with cognitive function, we propose targeting of Ng expression as a promising strategy to prevent or alleviate the cognitive deficits associated with aging and neuropathological conditions.


Neurogranin Synaptic plasticity Glutamate receptors Synaptogenesis Hippocampal neurons 



We thank Dr. FG Scholl (IBiS, Sevilla, Spain) and P. Scheifelle (Biozentrum, Basel, Switzerland) for providing the lentivector pLOX-Syn-DsRed-Syn-GFP. We would like to thank the Advanced Light Microscopy Core Facility, from Centro de Biología Molecular Severo Ochoa (CSIC-UAM), for assistance with the imaging studies.

Author Contributions

AG-G, RA, AJ-P, PS, DS-F, and EM-B carried out the experiments and analyzed the data. FJD-G conceived the study and wrote the manuscript. All the authors have read and approved the final version of the manuscript submitted.

Funding Information

This work was supported by the Spanish Ministry of Science and Innovation and MINECO (grants BFU2010-18297 and SAF2014- 55686-R). We also thank the “Fundación Ramón Areces” for providing institutional support to CBMSO.

Compliance with Ethical Standards

All procedures were carried out in accordance with the Spanish Royal Decree 1201/2005 for the protection of animals used in scientific research, and the European Union Directive 2010/63/EU regarding the protection of animals used for scientific purposes. The procedures were approved by local Ethical Committees.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary Figure 1

Maturation profiles of several proteins in cultured hippocampal neurons. Hippocampal neurons were harvested at several times of culture and processed for western blot; equal amounts of total protein were loaded from samples collected at each day in vitro (DIV). Antibodies used are listed in Supplementary Table 1. (PNG 926 kb)

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Supplementary Figure 2

Distribution of excitatory and inhibitory neurons in hippocampal neurons in culture. DIV16 hippocampal neurons were fixed and processed for immunofluorescence. 10 x 10 images were acquired with a 25X oil objective for each channel (DAPI, MAP 2, GluN1, GAD6) and stitched using Metamorph software. Upper panel shows complete tilescans of the total number of cells (DAPI), total number of neurons (MAP 2), excitatory neurons (GluN1), and inhibitory neurons (GAD6). White square shows the ROI detailed in the lower panel. Only a small proportion (11,41% ±3,43 SD n = 2) of neurons in culture expressed the inhibitory marker GAD6 when quantified, while the vast majority (82,55% ±1,41 SD n = 2) were excitatory neurons and expressed GluN1 marker. (PNG 3355 kb)

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Supplementary Figure 3

Example of the dense network of excitatory buttons in hippocampal neurons in culture. Immunofluorescence showing DIV16 hippocampal neurons labeled with DAPI, NeuN and vGluT1 antibodies. Note the dense network of excitatory synapses labeled with anti-vGluT1 antibody. (PNG 3010 kb)

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Supplementary Figure 4

Ng is expressed in a reduced fraction of hippocampal neurons in culture. DIV16 hippocampal neurons were fixed and processed for immunofluorescence. 10 x 10 images were acquired with a 25X oil objective for each channel (DAPI, MAP 2, Ng, GFAP) and stitched using Metamorph software. Upper panel shows complete tilescans of the total number of cells (DAPI), total number of neurons (MAP 2), Ng expressing neurons (Ng), and astrocytes (GFAP). White square shows the ROI detailed in the lower panel. (PNG 2999 kb)

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Supplementary Figure 5

Ng localizes to the dendritic spines of cultured hippocampal neurons. (Upper panel) Immunofluorescence showing a hippocampal neuron after 18 days in vitro (DIV) labeled with anti-Ng antibody and several other cells labeled only with DAPI. (Lower panel) Detail of Ng-labeled dendrites and dendritic spines (red arrowheads). (PNG 1551 kb)

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Supplementary Figure 6.

Analysis of Ng-expressing cells in cultured hippocampal neurons. Hippocampal neurons cultured at different cell densities were processed for immunofluorescence with anti-NeuN, anti-Ng antibodies and DAPI. 15 x 15 images covering a central rectangle (7.2 x 5.7 mm) of each coverslip were acquired for each channel and stitched using Metamorph software. Then, for each coverslip, cell density and time of culture (see Fig. 2c), total number of cells (DAPI), total number of neurons (NeuN/DAPI) and total number of Ng-expressing neurons (Ng/NeuN) were measured. The table below gives the total number of cells analyzed at each cell density and the percentage of those that were identified as neurons. (PNG 1016 kb)

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Supplementary Figure 7.

Long-term manipulation of endogenous synaptic activity modulates Ng expression. Examples of the western blots quantified for Fig. 4b. Hippocampal neurons were treated as in stated in fig. 4a for the indicated periods, starting at different times and all them collected at DIV18 for western blot analysis. (PNG 802 kb)

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Supplementary Figure 8.

Long-term manipulation of endogenous activity alters postsynaptic composition. Hippocampal neurons were kept in control medium or treated with tetrodotoxin (0′5 μM) or bicuculline (25 μM) for 48 h and extracted at DIV18. PSD fractions were purified as described in Methods. 4 μg of total protein of post-synaptic membrane-enriched fractions (Triton X-100 resistant pellet, TxP) were separated by SDS-PAGE and analyzed by western blot with anti-GluN1 (NR1, Millipore AB9864R), anti-GluN2B (NR2B, Millipore MAB5220), anti-PKCɛ (Millipore 06-991) and anti-β-actin (Sigma clone AC-15). (PNG 214 kb)

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Supplementary Figure 9.

Recovery of Ng expression after long-term treatment with AP5, TTX and NBQX. Hippocampal neurons were treated with 50 μM AP5, 1 μM TTX, AP5 + TTX or 10 μM NBQX for 1, 2 or 3 days and then harvested after 18 days in vitro (DIV18) for western blot analysis of their Ng and β3-tubulin content. Additionally, hippocampal neurons that were previously treated (Rec.) or not (Cont.) for 3 days with the above drugs were cultured for 3 additional days in normal growth medium (without drugs) and then collected to analyze recovery of Ng expression. Results are expressed as the ratio of Ng:β3-tubulin normalized to the ratio obtained for controls at DIV18. Results are means ± SEM, n = 5. Statistical comparisons were performed between each treatment and the corresponding controls at DIV18. *: p < 0.05, **: p < 0.01, ***: p < 0.001. (PNG 238 kb)

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Supplementary Figure 10.

Effect of several inhibitors on Ng levels after cLTP and cLTD induction. Cultured hippocampal neurons after 17 or 18 days in vitro (DIV) were processed for induction of (a) chemical long-term potentiation (cLTP) or (b) chemical long-term depression (cLTD). Lysates were obtained at the indicated times of the recovery period to analyze their Ng content by western blot. Inhibitors (MG132, 10 μM; anisomycin, 40 μM; calpeptin, 10 μM; cycloheximide [CHX], 25 μg/ml; AP5, 100 μM; NBQX, 20 μM; and MCPG, 125 μM) were added 15 min before cLTP induction and maintained thereafter (means ± SEM, n = 3). Statistical comparisons were performed between each treatment and the corresponding controls at DIV18. *: p < 0.05, **: p < 0.01, ***: p < 0.001. (PNG 285 kb)

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Supplementary Figure 11

Flowchart of the image analysis procedure used to quantify synaptogenesis in hippocampal neurons in culture. (PNG 1020 kb)

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Supplementary Figure 12

Typical captures for analyzing excitatory synapses. Hippocampal neurons were fixed and processed for immunofluorescence at DIV18. Upper panel shows typical example images labeling of MAP 2, vGluT1 and PSD-95, used for the synaptogenesis analysis in Fig. 6. White squares in the merge image show the ROIs detailed in the lower panel. (PNG 2561 kb)

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Supplementary Table 1 (DOCX 17 kb)


  1. 1.
    Diez-Guerra FJ (2010) Neurogranin, a link between calcium/calmodulin and protein kinase C signaling in synaptic plasticity. IUBMB Life 62(8):597–606. CrossRefPubMedGoogle Scholar
  2. 2.
    Alvarez-Bolado G, Rodriguez-Sanchez P, Tejero-Diez P, Fairen A, Diez-Guerra FJ (1996) Neurogranin in the development of the rat telencephalon. Neuroscience 73(2):565–580CrossRefGoogle Scholar
  3. 3.
    Represa A, Deloulme JC, Sensenbrenner M, Ben-Ari Y, Baudier J (1990) Neurogranin: immunocytochemical localization of a brain-specific protein kinase C substrate. J Neurosci 10(12):3782–3792CrossRefGoogle Scholar
  4. 4.
    Watson JB, Sutcliffe JG, Fisher RS (1992) Localization of the protein kinase C phosphorylation/calmodulin-binding substrate RC3 in dendritic spines of neostriatal neurons. Proc Natl Acad Sci U S A 89(18):8581–8585CrossRefGoogle Scholar
  5. 5.
    Prichard L, Deloulme JC, Storm DR (1999) Interactions between neurogranin and calmodulin in vivo. J Biol Chem 274(12):7689–7694CrossRefGoogle Scholar
  6. 6.
    Dominguez-Gonzalez I, Vazquez-Cuesta SN, Algaba A, Diez-Guerra FJ (2007) Neurogranin binds to phosphatidic acid and associates to cellular membranes. Biochem J 404(1):31–43. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Pak JH, Huang FL, Li J, Balschun D, Reymann KG, Chiang C, Westphal H, Huang KP (2000) Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice. Proc Natl Acad Sci U S A 97(21):11232–11237. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Huang KP, Huang FL, Jager T, Li J, Reymann KG, Balschun D (2004) Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci 24(47):10660–10669. CrossRefPubMedGoogle Scholar
  9. 9.
    Zhong L, Cherry T, Bies CE, Florence MA, Gerges NZ (2009) Neurogranin enhances synaptic strength through its interaction with calmodulin. EMBO J 28(19):3027–3039. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhabotinsky AM, Camp RN, Epstein IR, Lisman JE (2006) Role of the neurogranin concentrated in spines in the induction of long-term potentiation. J Neurosci 26(28):7337–7347. CrossRefPubMedGoogle Scholar
  11. 11.
    Krucker T, Siggins GR, McNamara RK, Lindsley KA, Dao A, Allison DW, De Lecea L, Lovenberg TW et al (2002) Targeted disruption of RC3 reveals a calmodulin-based mechanism for regulating metaplasticity in the hippocampus. J Neurosci 22(13):5525–5535CrossRefGoogle Scholar
  12. 12.
    Miyakawa T, Yared E, Pak JH, Huang FL, Huang KP, Crawley JN (2001) Neurogranin null mutant mice display performance deficits on spatial learning tasks with anxiety related components. Hippocampus 11(6):763–775. CrossRefPubMedGoogle Scholar
  13. 13.
    Clayton DF, George JM, Mello CV, Siepka SM (2009) Conservation and expression of IQ-domain-containing calpacitin gene products (neuromodulin/GAP-43, neurogranin/RC3) in the adult and developing oscine song control system. Dev Neurobiol 69(2–3):124–140. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Salazar P, Cisternas P, Martinez M, Inestrosa NC (2018) Hypothyroidism and cognitive disorders during development and adulthood: implications in the central nervous system. Mol Neurobiol. CrossRefGoogle Scholar
  15. 15.
    Iniguez MA, Rodriguez-Pena A, Ibarrola N, Morreale de Escobar G, Bernal J (1992) Adult rat brain is sensitive to thyroid hormone. Regulation of RC3/neurogranin mRNA. J Clin Invest 90(2):554–558. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Iniguez MA, De Lecea L, Guadano-Ferraz A, Morte B, Gerendasy D, Sutcliffe JG, Bernal J (1996) Cell-specific effects of thyroid hormone on RC3/neurogranin expression in rat brain. Endocrinology 137(3):1032–1041. CrossRefPubMedGoogle Scholar
  17. 17.
    Havekes R, Park AJ, Tudor JC, Luczak VG, Hansen RT, Ferri SL, Bruinenberg VM, Poplawski SG et al (2016) Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1. Elife 5.
  18. 18.
    Yoo SS, Hu PT, Gujar N, Jolesz FA, Walker MP (2007) A deficit in the ability to form new human memories without sleep. Nat Neurosci 10(3):385–392. CrossRefPubMedGoogle Scholar
  19. 19.
    Neuner-Jehle M, Rhyner TA, Borbely AA (1995) Sleep deprivation differentially alters the mRNA and protein levels of neurogranin in rat brain. Brain Res 685(1–2):143–153CrossRefGoogle Scholar
  20. 20.
    Lynch G, Rex CS, Gall CM (2006) Synaptic plasticity in early aging. Ageing Res Rev 5(3):255–280. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mons N, Enderlin V, Jaffard R, Higueret P (2001) Selective age-related changes in the PKC-sensitive, calmodulin-binding protein, neurogranin, in the mouse brain. J Neurochem 79(4):859–867CrossRefGoogle Scholar
  22. 22.
    Boucheron C, Alfos S, Enderlin V, Husson M, Pallet V, Jaffard R, Higueret P (2006) Age-related effects of ethanol consumption on triiodothyronine and retinoic acid nuclear receptors, neurogranin and neuromodulin expression levels in mouse brain. Neurobiol Aging 27(9):1326–1334. CrossRefGoogle Scholar
  23. 23.
    Wellington H, Paterson RW, Portelius E, Tornqvist U, Magdalinou N, Fox NC, Blennow K, Schott JM et al (2016) Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86(9):829–835. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kester MI, Teunissen CE, Crimmins DL, Herries EM, Ladenson JH, Scheltens P, van der Flier WM, Morris JC et al (2015) Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease. JAMA Neurol 72(11):1275–1280. CrossRefGoogle Scholar
  25. 25.
    Headley A, De Leon-Benedetti A, Dong C, Levin B, Loewenstein D, Camargo C, Rundek T, Zetterberg H et al (2018) Neurogranin as a predictor of memory and executive function decline in MCI patients. Neurology 90(10):e887–e895. CrossRefGoogle Scholar
  26. 26.
    Portelius E, Zetterberg H, Skillback T, Tornqvist U, Andreasson U, Trojanowski JQ, Weiner MW, Shaw LM et al (2015) Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease. Brain 138(Pt 11):3373–3385. CrossRefGoogle Scholar
  27. 27.
    Kvartsberg H, Duits FH, Ingelsson M, Andreasen N, Ohrfelt A, Andersson K, Brinkmalm G, Lannfelt L et al (2015) Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer’s disease. Alzheimers Dement 11(10):1180–1190. CrossRefGoogle Scholar
  28. 28.
    Lashley T, Schott JM, Weston P, Murray CE, Wellington H, Keshavan A, Foti SC, Foiani M et al (2018) Molecular biomarkers of Alzheimer’s disease: progress and prospects. Dis Model Mech 11(5):dmm031781. CrossRefGoogle Scholar
  29. 29.
    Gascon S, Paez-Gomez JA, Diaz-Guerra M, Scheiffele P, Scholl FG (2008) Dual-promoter lentiviral vectors for constitutive and regulated gene expression in neurons. J Neurosci Methods 168(1):104–112. CrossRefPubMedGoogle Scholar
  30. 30.
    Kaech S, Banker G (2006) Culturing hippocampal neurons. Nat Protoc 1(5):2406–2415. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ulloa L, Ibarrola N, Avila J, Diez-Guerra FJ (1994) Microtubule-associated protein 1B (MAP 1B) is present in glial cells phosphorylated different than in neurones. Glia 10(4):266–275. CrossRefPubMedGoogle Scholar
  32. 32.
    Oh MC, Derkach VA (2005) Dominant role of the GluR2 subunit in regulation of AMPA receptors by CaMKII. Nat Neurosci 8(7):853–854. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lu W, Man H, Ju W, Trimble WS, MacDonald JF, Wang YT (2001) Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29(1):243–254CrossRefGoogle Scholar
  34. 34.
    Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC (2000) Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat Neurosci 3(12):1291–1300. CrossRefPubMedGoogle Scholar
  35. 35.
    Tejero-Diez P, Rodriguez-Sanchez P, Diez-Guerra FJ (1999) Microscale purification of proteins exhibiting anomalous electrophoretic migration: application to the analysis of GAP-43 phosphorylation. Anal Biochem 274(2):278–282. CrossRefPubMedGoogle Scholar
  36. 36.
    Davies KD, Goebel-Goody SM, Coultrap SJ, Browning MD (2008) Long term synaptic depression that is associated with GluR1 dephosphorylation but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. J Biol Chem 283(48):33138–33146. CrossRefGoogle Scholar
  37. 37.
    Basarsky TA, Parpura V, Haydon PG (1994) Hippocampal synaptogenesis in cell culture: developmental time course of synapse formation, calcium influx, and synaptic protein distribution. J Neurosci 14(11 Pt 1):6402–6411CrossRefGoogle Scholar
  38. 38.
    Grabrucker A, Vaida B, Bockmann J, Boeckers TM (2009) Synaptogenesis of hippocampal neurons in primary cell culture. Cell Tissue Res 338(3):333–341. CrossRefGoogle Scholar
  39. 39.
    Benson DL, Watkins FH, Steward O, Banker G (1994) Characterization of GABAergic neurons in hippocampal cell cultures. J Neurocytol 23(5):279–295CrossRefGoogle Scholar
  40. 40.
    Singec I, Knoth R, Ditter M, Volk B, Frotscher M (2004) Neurogranin is expressed by principal cells but not interneurons in the rodent and monkey neocortex and hippocampus. J Comp Neurol 479(1):30–42. CrossRefPubMedGoogle Scholar
  41. 41.
    Ivenshitz M, Segal M (2010) Neuronal density determines network connectivity and spontaneous activity in cultured hippocampus. J Neurophysiol 104(2):1052–1060. CrossRefPubMedGoogle Scholar
  42. 42.
    Clarke LE, Barres BA (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14(5):311–321. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Banker GA (1980) Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 209(4458):809–810CrossRefGoogle Scholar
  44. 44.
    Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294(5545):1354–1357. CrossRefPubMedGoogle Scholar
  45. 45.
    Goritz C, Mauch DH, Pfrieger FW (2005) Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron. Mol Cell Neurosci 29(2):190–201. CrossRefPubMedGoogle Scholar
  46. 46.
    Bardy C, van den Hurk M, Eames T, Marchand C, Hernandez RV, Kellogg M, Gorris M, Galet B et al (2015) Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc Natl Acad Sci U S A 112(20):E2725–E2734. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Martinez de Arrieta C, Morte B, Coloma A, Bernal J (1999) The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron. Endocrinology 140(1):335–343. CrossRefPubMedGoogle Scholar
  48. 48.
    Enderlin V, Vallortigara J, Alfos S, Feart C, Pallet V, Higueret P (2004) Retinoic acid reverses the PTU related decrease in neurogranin level in mice brain. J Physiol Biochem 60(3):191–198CrossRefGoogle Scholar
  49. 49.
    Guadano-Ferraz A, Escamez MJ, Morte B, Vargiu P, Bernal J (1997) Transcriptional induction of RC3/neurogranin by thyroid hormone: differential neuronal sensitivity is not correlated with thyroid hormone receptor distribution in the brain. Brain Res Mol Brain Res 49(1–2):37–44CrossRefGoogle Scholar
  50. 50.
    Vicario-Abejon C, Collin C, McKay RD, Segal M (1998) Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. J Neurosci 18(18):7256–7271CrossRefGoogle Scholar
  51. 51.
    Vicario-Abejon C, Johe KK, Hazel TG, Collazo D, McKay RD (1995) Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons. Neuron 15(1):105–114CrossRefGoogle Scholar
  52. 52.
    Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G et al (2010) A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107(6):2687–2692. CrossRefGoogle Scholar
  53. 53.
    Turrigiano G (2012) Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol 4(1):a005736. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Murthy VN, Schikorski T, Stevens CF, Zhu Y (2001) Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32(4):673–682CrossRefGoogle Scholar
  55. 55.
    Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6(3):231–242. CrossRefPubMedGoogle Scholar
  56. 56.
    Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998) Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391(6670):892–896. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Bingol B, Sheng M (2011) Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease. Neuron 69(1):22–32. CrossRefPubMedGoogle Scholar
  58. 58.
    Becker B, Nazir FH, Brinkmalm G, Camporesi E, Kvartsberg H, Portelius E, Bostrom M, Kalm M et al (2018) Alzheimer-associated cerebrospinal fluid fragments of neurogranin are generated by calpain-1 and prolyl endopeptidase. Mol Neurodegener 13(1):47.
  59. 59.
    Chang JW, Schumacher E, Coulter PM 2nd, Vinters HV, Watson JB (1997) Dendritic translocation of RC3/neurogranin mRNA in normal aging, Alzheimer disease and fronto-temporal dementia. J Neuropathol Exp Neurol 56(10):1105–1118CrossRefGoogle Scholar
  60. 60.
    Gao Y, Tatavarty V, Korza G, Levin MK, Carson JH (2008) Multiplexed dendritic targeting of alpha calcium calmodulin-dependent protein kinase II, neurogranin, and activity-regulated cytoskeleton-associated protein RNAs by the A2 pathway. Mol Biol Cell 19(5):2311–2327. CrossRefGoogle Scholar
  61. 61.
    Schuman EM, Dynes JL, Steward O (2006) Synaptic regulation of translation of dendritic mRNAs. J Neurosci 26(27):7143–7146. CrossRefPubMedGoogle Scholar
  62. 62.
    Jones KJ, Templet S, Zemoura K, Kuzniewska B, Pena FX, Hwang H, Lei DJ, Haensgen H et al (2018) Rapid, experience-dependent translation of neurogranin enables memory encoding. Proc Natl Acad Sci U S A 115(25):E5805–E5814. CrossRefGoogle Scholar
  63. 63.
    Garrido-Garcia A, Andres-Pans B, Duran-Trio L, Diez-Guerra FJ (2009) Activity-dependent translocation of neurogranin to neuronal nuclei. Biochem J 424(3):419–429. CrossRefPubMedGoogle Scholar
  64. 64.
    Han KS, Cooke SF, Xu W (2017) Experience-dependent equilibration of AMPAR-mediated synaptic transmission during the critical period. Cell Rep 18(4):892–904. CrossRefPubMedGoogle Scholar
  65. 65.
    Gerendasy DD, Sutcliffe JG (1997) RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes. Mol Neurobiol 15(2):131–163CrossRefGoogle Scholar
  66. 66.
    Huang FL, Huang KP, Wu J, Boucheron C (2006) Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. J Neurosci 26(23):6230–6237. CrossRefPubMedGoogle Scholar
  67. 67.
    Bernal J (2000) Thyroid hormones in brain development and function. In: De Groot LJ, Chrousos G, Dungan K et al (eds) Endotext. South Dartmouth (MA)Google Scholar
  68. 68.
    Koromilas C, Liapi C, Schulpis KH, Kalafatakis K, Zarros A, Tsakiris S (2010) Structural and functional alterations in the hippocampus due to hypothyroidism. Metab Brain Dis 25(3):339–354. CrossRefPubMedGoogle Scholar
  69. 69.
    Kvartsberg H, Lashley T, Murray CE, Brinkmalm G, Cullen NC, Hoglund K, Zetterberg H, Blennow K et al (2018) The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer’s disease. Acta Neuropathol 137:89–102. CrossRefGoogle Scholar
  70. 70.
    Cohen E, Ivenshitz M, Amor-Baroukh V, Greenberger V, Segal M (2008) Determinants of spontaneous activity in networks of cultured hippocampus. Brain Res 1235:21–30. CrossRefPubMedGoogle Scholar
  71. 71.
    Arnold FJ, Hofmann F, Bengtson CP, Wittmann M, Vanhoutte P, Bading H (2005) Microelectrode array recordings of cultured hippocampal networks reveal a simple model for transcription and protein synthesis-dependent plasticity. J Physiol 564(Pt 1):3–19. CrossRefPubMedGoogle Scholar
  72. 72.
    Frotscher M, Heimrich B (1993) Formation of layer-specific fiber projections to the hippocampus in vitro. Proc Natl Acad Sci U S A 90(21):10400–10403CrossRefGoogle Scholar
  73. 73.
    Hardingham GE, Arnold FJ, Bading H (2001) A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nat Neurosci 4(6):565–566. CrossRefGoogle Scholar
  74. 74.
    Rao A, Craig AM (1997) Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19(4):801–812CrossRefGoogle Scholar
  75. 75.
    Chowdhury D, Hell JW (2018) Homeostatic synaptic scaling: molecular regulators of synaptic AMPA-type glutamate receptors. F1000Res 7:234. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Martzen MR, Slemmon JR (1995) The dendritic peptide neurogranin can regulate a calmodulin-dependent target. J Neurochem 64(1):92–100CrossRefGoogle Scholar
  77. 77.
    Zhong L, Gerges NZ (2010) Neurogranin and synaptic plasticity balance. Commun Integr Biol 3(4):340–342CrossRefGoogle Scholar
  78. 78.
    Krueger DD, Nairn AC (2007) Expression of PKC substrate proteins, GAP-43 and neurogranin, is downregulated by cAMP signaling and alterations in synaptic activity. Eur J Neurosci 26(11):3043–3053. CrossRefPubMedGoogle Scholar
  79. 79.
    Hensch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6(11):877–888. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Jeon SG, Kang M, Kim YS, Kim DH, Nam DW, Song EJ, Mook-Jung I, Moon M (2018) Intrahippocampal injection of a lentiviral vector expressing neurogranin enhances cognitive function in 5XFAD mice. Exp Mol Med 50(3):e461. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alberto Garrido-García
    • 1
    • 2
  • Raquel de Andrés
    • 1
  • Amanda Jiménez-Pompa
    • 1
    • 3
  • Patricia Soriano
    • 1
  • Diego Sanz-Fuentes
    • 1
  • Elena Martínez-Blanco
    • 1
  • F. Javier Díez-Guerra
    • 1
    • 4
    Email author
  1. 1.Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC)Universidad Autónoma de MadridMadridSpain
  2. 2.Instituto Cajal (CSIC)MadridSpain
  3. 3.Departamento de Farmacología y Terapéutica, Facultad de MedicinaUniversidad Autónoma de MadridMadridSpain
  4. 4.Laboratory of Neuronal Plasticity, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)Universidad Autónoma de MadridMadridSpain

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