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Cited by 49Neuroscience and Neuropharmacology ResearchSchizophrenia research and treatmentGenetics and Neurodevelopmental Disorders

Neurogranin, Encoded by the Schizophrenia Risk Gene NRGN, Bidirectionally Modulates Synaptic Plasticity via Calmodulin-Dependent Regulation of the Neuronal Phosphoproteome

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Hwang, Hongik, Szucs, Matthew J., Ding, Lei J., Allen, Andrew, Ren, Xiaobai, Haensgen, Henny, Gao, Fan, Rhim, Hyewhon +5 more·2021·Biological Psychiatry
DOI 10.1016/j.biopsych.2020.07.014PMC PMC9258036
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Abstract

Background Neurogranin (Ng), encoded by the schizophrenia risk gene NRGN, is a calmodulin-binding protein enriched in the postsynaptic compartments, and its expression is reduced in the postmortem brains of patients with schizophrenia. Experience-dependent translation of Ng is critical for encoding contextual memory, and Ng regulates developmental plasticity in the primary visual cortex during the critical period. However, the overall impact of Ng on the neuronal signaling that regulates synaptic plasticity is unknown. Methods Altered Ng expression was achieved via virus-mediated gene manipulation in mice. The effect on long-term potentiation (LTP) was accessed using spike timing-dependent plasticity protocols. Quantitative phosphoproteomics analyses led to discoveries in significant phosphorylated targets. An identified candidate was examined with high-throughput planar patch clamp and was validated with pharmacological manipulation. Results Ng bidirectionally modulated LTP in the hippocampus. Decreasing Ng levels significantly affected the phosphorylation pattern of postsynaptic density proteins, including glutamate receptors, GTPases, kinases, RNA binding proteins, selective ion channels, and ionic transporters, some of which highlighted clusters of schizophrenia- and autism-related genes. Hypophosphorylation of NMDA receptor subunit Grin2A, one significant phosphorylated target, resulted in accelerated decay of NMDA receptor currents. Blocking protein phosphatase PP2B activity rescued the accelerated NMDA receptor current decay and the impairment of LTP mediated by Ng knockdown, implicating the requirement of synaptic PP2B activity for the deficits. Conclusions Altered Ng levels affect the phosphorylation landscape of neuronal proteins. PP2B activity is required for mediating the deficit in synaptic plasticity caused by decreasing Ng levels, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.

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  1. [1]Freedman R (2003): Schizophrenia. N Engl J Med 349: 1738– 1749. 14585943
  2. [2]Lopez AD, Murray CC (1998): The global burden of disease, 1990–2020. Nat Med 4: 1241– 1243. 9809543
  3. [4]Sullivan PF, Kendler KS, Neale MC (2003): Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60: 1187– 1192. 14662550
  4. [6]Schizophrenia Working Group of the Psychiatric Genomics C (2014): Biological insights from 108 schizophrenia-associated genetic loci. Nature 511: 421– 427. 25056061 PMC4112379
  5. [8]International Schizophrenia C, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, (2009): Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460: 748– 752. 19571811 PMC3912837
  6. [10]Ikeda M, Aleksic B, Kinoshita Y, Okochi T, Kawashima K, Kushima I, (2011): Genome-wide association study of schizophrenia in a Japanese population. Biol Psychiatry 69: 472– 478. 20832056
  7. [11]Schizophrenia Psychiatric Genome-Wide Association Study C (2011): Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43: 969– 976. 21926974 PMC3303194
  8. [12]Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, (2009): Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460: 753– 757. 19571809 PMC2775422
  9. [13]Yue WH, Wang HF, Sun LD, Tang FL, Liu ZH, Zhang HX, (2011): Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet 43: 1228– 1231. 22037552
  10. [14]Rietschel M, Mattheisen M, Degenhardt F, Genetic R, Outcome in P, Muhleisen TW, (2012): Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Mol Psychiatry 17: 906– 917. 21747397
  11. [15]Ohi K, Hashimoto R, Yasuda Y, Fukumoto M, Yamamori H, Umeda-Yano S, (2012): Functional genetic variation at the NRGN gene and schizophrenia: evidence from a gene-based case-control study and gene expression analysis. Am J Med Genet B Neuropsychiatr Genet 159B: 405– 413. 22461181
  12. [16]Ohi K, Hashimoto R, Yasuda Y, Fukumoto M, Yamamori H, Umeda-Yano S, (2013): Influence of the NRGN gene on intellectual ability in schizophrenia. J Hum Genet, pp 700– 705. 23903071
  13. [17]Ruano D, Aulchenko YS, Macedo A, Soares MJ, Valente J, Azevedo MH, (2008): Association of the gene encoding neurogranin with schizophrenia in males. J Psychiatr Res, pp 125– 133. 17140601
  14. [18]Pohlack ST, Nees F, Ruttorf M, Witt SH, Nieratschker V, Rietschel M, (2011): Risk variant for schizophrenia in the neurogranin gene impacts on hippocampus activation during contextual fear conditioning. Mol Psychiatry, pp 1072– 1073. 21647148 PMC3199731
  15. [19]Ohi K, Hashimoto R, Yasuda Y, Nemoto K, Ohnishi T, Fukumoto M, (2012): Impact of the genome wide supported NRGN gene on anterior cingulate morphology in schizophrenia. PLoS ONE, pp e29780. 22253779 PMC3257237
  16. [20]Broadbelt K, Ramprasaud A, Jones LB (2006): Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. Schizophr Res, pp 6– 14. 16797925
  17. [21]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, pp 3043– 3053. 18005072
  18. [22]Neuner-Jehle M, Denizot JP, Mallet J (1996): Neurogranin is locally concentrated in rat cortical and hippocampal neurons. Brain Res, pp 149– 154. 8891262
  19. [23]Ressler KJ, Paschall G, Zhou X-l, Davis M (2002): Regulation of synaptic plasticity genes during consolidation of fear conditioning. J Neurosci, pp 7892– 7902. 12223542 PMC6758105
  20. [24]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, pp 3782– 3792. 2269883 PMC6570038
  21. [25]Han KS, Cooke SF, Xu W (2017): Experience-Dependent Equilibration of AMPAR-Mediated Synaptic Transmission during the Critical Period. Cell Rep 18: 892– 904. 28122240
  22. [26]Jones KJ, Templet S, Zemoura K, Kuzniewska B, Pena FX, Hwang H, (2018): Rapid, experience-dependent translation of neurogranin enables memory encoding. Proc Natl Acad Sci U S A 115: E5805– E5814. 29880715 PMC6016824
  23. [27]Gerendasy D (1999): Homeostatic tuning of Ca2+ signal transduction by members of the calpacitin protein family. J Neurosci Res, pp 107– 119. 10491576
  24. [28]Slemmon JR, Feng B, Erhardt JA (2000): Small proteins that modulate calmodulin-dependent signal transduction: effects of PEP-19, neuromodulin, and neurogranin on enzyme activation and cellular homeostasis. Mol Neurobiol: Humana Press, pp 99– 113. 11414283
  25. [29]Malinow R, Schulman H, Tsien RW (1989): Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245: 862– 866. 2549638
  26. [31]Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, Malinow R (2014): Engineering a memory with LTD and LTP. Nature 511: 348– 352. 24896183 PMC4210354
  27. [32]Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006): Learning induces long-term potentiation in the hippocampus. Science 313: 1093– 1097. 16931756
  28. [33]Xia Z, Storm DR (2005): The role of calmodulin as a signal integrator for synaptic plasticity. Nat Rev Neurosci 6: 267– 276. 15803158
  29. [34]Shepherd JD, Huganir RL (2007): The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23: 613– 643. 17506699
  30. [35]Malenka RC, Bear MF (2004): LTP and LTD: an embarrassment of riches. Neuron 44: 5– 21. 15450156
  31. [36]Kauer JA, Malenka RC (2007): Synaptic plasticity and addiction. Nat Rev Neurosci 8: 844– 858. 17948030
  32. [37]Lisman JE (2001): Three Ca2+ levels affect plasticity differently: the LTP zone, the LTD zone and no man’s land. J Physiol 532: 285. 11306649 PMC2278561
  33. [38]Lisman J, Schulman H, Cline H (2002): The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3: 175– 190. 11994750
  34. [39]Bayer KU, Schulman H (2019): CaM Kinase: Still Inspiring at 40. Neuron 103: 380– 394. 31394063 PMC6688632
  35. [40]Kennedy MB (2000): Signal-processing machines at the postsynaptic density. Science 290: 750– 754. 11052931
  36. [41]Wang JH, Kelly PT (1996): The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. Learn Mem 3: 170– 181. 10456087
  37. [42]Seol GH, Ziburkus J, Huang S, Song L, Kim IT, Takamiya K, (2007): Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity. Neuron, pp 919– 929. PMC2756178 17880895
  38. [43]Woolfrey KM, Dell’Acqua ML (2015): Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity. J Biol Chem 290: 28604– 28612. 26453308 PMC4661375
  39. [44]Ouyang Y, Rosenstein A, Kreiman G, Schuman EM, Kennedy MB (1999): Tetanic stimulation leads to increased accumulation of Ca(2+)/calmodulin-dependent protein kinase II via dendritic protein synthesis in hippocampal neurons. J Neurosci 19: 7823– 7833. 10479685 PMC6782482
  40. [45]De Koninck P, Schulman H (1998): Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279: 227– 230. 9422695
  41. [46]Ouyang Y, Kantor D, Harris KM, Schuman EM, Kennedy MB (1997): Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus. J Neurosci 17: 5416– 5427. 9204925 PMC6793833
  42. [47]Rich RC, Schulman H (1998): Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 273: 28424– 28429. 9774470
  43. [48]Miller SG, Kennedy MB (1986): Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch. Cell 44: 861– 870. 3006921
  44. [49]Schulman H (2004): Activity-dependent regulation of calcium/calmodulin-dependent protein kinase II localization. J Neurosci 24: 8399– 8403. 15456811 PMC6729891
  45. [50]Quintana AR, Wang D, Forbes JE, Waxham MN (2005): Kinetics of calmodulin binding to calcineurin. Biochem Biophys Res Commun 334: 674– 680. 16009337
  46. [51]Chen X, Vinade L, Leapman RD, Petersen JD, Nakagawa T, Phillips TM, (2005): Mass of the postsynaptic density and enumeration of three key molecules. Proc Natl Acad Sci U S A 102: 11551– 11556. 16061821 PMC1182136
  47. [52]Collins MO, Husi H, Yu L, Brandon JM, Anderson CN, Blackstock WP, (2006): Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J Neurochem 97 Suppl 1: 16– 23. 16635246
  48. [53]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: Society for Neuroscience, pp 7337– 7347. 16837580 PMC6674191
  49. [54]Gerendasy DD, Sutcliffe JG (1997): RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes. Mol Neurobiol, pp 131– 163. 9396008
  50. [55]Huang K-P, Huang FL, Jäger T, Li J, Reymann KG, Balschun D (2004): Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci: Society for Neuroscience, pp 10660– 10669. 15564582 PMC6730132
  51. [56]van Dalen JJW, Gerendasy DD, de Graan PNE, Schrama LH, Gruol DL (2003): Calcium dynamics are altered in cortical neurons lacking the calmodulin-binding protein RC3. Eur J Neurosci, pp 13– 22. 12859333
  52. [57]Zhong L, Cherry T, Bies CE, Florence MA, Gerges NZ (2009): Neurogranin enhances synaptic strength through its interaction with calmodulin. EMBO J, pp 3027– 3039. 19713936 PMC2736013
  53. [58]Zhong L, Gerges NZ (2012): Neurogranin targets calmodulin and lowers the threshold for the induction of long-term potentiation. PLoS ONE: Public Library of Science, pp e41275. 22848456 PMC3405117
  54. [59]Liu M, Lewis LD, Shi R, Brown EN, Xu W (2014): Differential requirement for NMDAR activity in SAP97β-mediated regulation of the number and strength of glutamatergic AMPAR-containing synapses. J Neurophysiol, pp 648– 658. 24225540 PMC3921414
  55. [60]Pan JQ, Baez-Nieto D, Allen A, Wang HR, Cottrell JR (2018): Developing High-Throughput Assays to Analyze and Screen Electrophysiological Phenotypes. Methods Mol Biol 1787: 235– 252. 29736723
  56. [61]Schluter OM, Xu W, Malenka RC (2006): Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron 51: 99– 111. 16815335
  57. [62]Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D (2002): Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295: 868– 872. 11786607
  58. [63]Kinoshita E, Kinoshita-Kikuta E, Koike T (2009): Separation and detection of large phosphoproteins using Phos-tag SDS-PAGE. Nat Protoc: Nature Publishing Group, pp 1513– 1521. 19798084
  59. [64]Kinoshita E, Kinoshita-Kikuta E, Takiyama K, Koike T (2006): Phosphate-binding tag, a new tool to visualize phosphorylated proteins. Mol Cell Proteomics 5: 749– 757. 16340016
  60. [65]Makino Y, Johnson RC, Yu Y, Takamiya K, Huganir RL (2011): Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. Proc Natl Acad Sci USA: National Acad Sciences, pp 8450– 8455. 21536866 PMC3100939
  61. [66]Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, (2013): Integrated proteomic analysis of post-translational modifications by serial enrichment. Nat Methods 10: 634– 637. 23749302 PMC3943163
  62. [67]Rappsilber J, Mann M, Ishihama Y (2007): Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2: 1896– 1906. 17703201
  63. [68]Cox J, Mann M (2011): Quantitative, high-resolution proteomics for data-driven systems biology. Annu Rev Biochem 80: 273– 299. 21548781
  64. [69]Elias JE, Gibbons FD, King OD, Roth FP, Gygi SP (2004): Intensity-based protein identification by machine learning from a library of tandem mass spectra. Nat Biotechnol 22: 214– 219. 14730315
  65. [70]Nesvizhskii AI, Aebersold R (2005): Interpretation of shotgun proteomic data: the protein inference problem. Mol Cell Proteomics 4: 1419– 1440. 16009968
  66. [71]Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, (2015): limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43: e47. 25605792 PMC4402510
  67. [72]Smyth GK (2004): Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3. 16646809
  68. [73]Bayes A, Collins MO, Croning MD, van de Lagemaat LN, Choudhary JS, Grant SG (2012): Comparative study of human and mouse postsynaptic proteomes finds high compositional conservation and abundance differences for key synaptic proteins. PLoS One 7: e46683. 23071613 PMC3465276
  69. [74]Yu G, Wang LG, Han Y, He QY (2012): clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16: 284– 287. 22455463 PMC3339379
  70. [75]Magee JC, Johnston D (1997): A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science, pp 209– 213. 8985013
  71. [76]Markram H, Lubke J, Frotscher M, Sakmann B (1997): Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275: 213– 215. 8985014
  72. [77]Bi GQ, Poo MM (1998): Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J Neurosci 18: 10464– 10472. 9852584 PMC6793365
  73. [78]Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, (2016): Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534: 55– 62. 27251275 PMC5102256
  74. [79]Mertins P, Yang F, Liu T, Mani DR, Petyuk VA, Gillette MA, (2014): Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics 13: 1690– 1704. 24719451 PMC4083109
  75. [80]Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, (2016): Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44: W90– 97. 27141961 PMC4987924
  76. [82]Gene Ontology C (2015): Gene Ontology Consortium: going forward. Nucleic Acids Res 43: D1049– 1056. 25428369 PMC4383973
  77. [83]Ashburner M, Lewis S (2002): On ontologies for biologists: the Gene Ontology--untangling the web. Novartis Found Symp 247: 66– 80; discussion 80–63, 84–90, 244–252. 12539950
  78. [84]Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP, (2019): SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse. Neuron 103: 217– 234 e214. 31171447 PMC6764089
  79. [87]Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, (1995): Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 373: 151– 155. 7816096
  80. [89]Shipton OA, Paulsen O (2014): GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond B Biol Sci 369: 20130163. 24298164 PMC3843894
  81. [90]Gerkin RC, Lau PM, Nauen DW, Wang YT, Bi GQ (2007): Modular competition driven by NMDA receptor subtypes in spike-timing-dependent plasticity. J Neurophysiol 97: 2851– 2862. 17267756
  82. [91]Hosokawa T, Mitsushima D, Kaneko R, Hayashi Y (2015): Stoichiometry and phosphoisotypes of hippocampal AMPA-type glutamate receptor phosphorylation. Neuron 85: 60– 67. 25533481 PMC4289098
  83. [92]Krupp JJ, Vissel B, Thomas CG, Heinemann SF, Westbrook GL (1999): Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate Ca2+-dependent inactivation of NMDA receptors. J Neurosci 19: 1165– 1178. 9952395 PMC6786025
  84. [93]Ehlers MD, Zhang S, Bernhadt JP, Huganir RL (1996): Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84: 745– 755. 8625412
  85. [94]Maki BA, Aman TK, Amico-Ruvio SA, Kussius CL, Popescu GK (2012): C-terminal domains of N-methyl-D-aspartic acid receptor modulate unitary channel conductance and gating. J Biol Chem 287: 36071– 36080. 22948148 PMC3476275
  86. [95]Krupp JJ, Vissel B, Thomas CG, Heinemann SF, Westbrook GL (2002): Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors. Neuropharmacology, pp 593– 602. 11985816
  87. [96]Shi J, Townsend M, Constantine-Paton M (2000): Activity-dependent induction of tonic calcineurin activity mediates a rapid developmental downregulation of NMDA receptor currents. Neuron, pp 103– 114. 11086987
  88. [97]Townsend M, Liu Y, Constantine-Paton M (2004): Retina-driven dephosphorylation of the NR2A subunit correlates with faster NMDA receptor kinetics at developing retinocollicular synapses. J Neurosci: Society for Neuroscience, pp 11098– 11107. 15590926 PMC6730286
  89. [98]Milligan CJ, Moller C (2013): Automated planar patch-clamp. Methods Mol Biol 998: 171– 187. 23529429
  90. [99]Szczepanowska J, Ramachandran U, Herring CJ, Gruschus JM, Qin J, Korn ED, (1998): Effect of mutating the regulatory phosphoserine and conserved threonine on the activity of the expressed catalytic domain of Acanthamoeba myosin I heavy chain kinase. Proc Natl Acad Sci U S A 95: 4146– 4151. 9539704 PMC22456
  91. [100]Littlepage LE, Wu H, Andresson T, Deanehan JK, Amundadottir LT, Ruderman JV (2002): Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A. Proc Natl Acad Sci U S A 99: 15440– 15445. 12422018 PMC137735
  92. [101]Zheng W, Zhang Z, Ganguly S, Weller JL, Klein DC, Cole PA (2003): Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation. Nat Struct Biol 10: 1054– 1057. 14578935
  93. [102]Dai H, Ding H, Meng XW, Lee SH, Schneider PA, Kaufmann SH (2013): Contribution of Bcl-2 phosphorylation to Bak binding and drug resistance. Cancer Res 73: 6998– 7008. 24097825 PMC3910374
  94. [103]Stefan MI, Edelstein SJ, Le Novère N (2008): An allosteric model of calmodulin explains differential activation of PP2B and CaMKII. Proc Natl Acad Sci USA: National Acad Sciences, pp 10768– 10773. 18669651 PMC2504824
  95. [104]Kim D, Hwang HY, Kim JY, Lee JY, Yoo JS, Marko-Varga G, (2017): FK506, an Immunosuppressive Drug, Induces Autophagy by Binding to the V-ATPase Catalytic Subunit A in Neuronal Cells. J Proteome Res 16: 55– 64. 28056508
  96. [106]Kolos JM, Voll AM, Bauder M, Hausch F (2018): FKBP Ligands-Where We Are and Where to Go? Front Pharmacol 9: 1425. 30568592 PMC6290070
  97. [107]Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, (2001): Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 107: 617– 629. 11733061
  98. [108]Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, (2001): Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104: 675– 686. 11257222
  99. [110]Huang KP, Huang FL, Li J, Schuck P, McPhie P (2000): Calcium-sensitive interaction between calmodulin and modified forms of rat brain neurogranin/RC3. Biochemistry, pp 7291– 7299. 10852729
  100. [111]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 USA, pp 8581– 8585. 1528865 PMC49964
  101. [112]Jones SL, To MS, Stuart GJ (2017): Dendritic small conductance calcium-activated potassium channels activated by action potentials suppress EPSPs and gate spike-timing dependent synaptic plasticity. Elife 6. PMC5679750 29058675
  102. [113]Liu X, Yang PS, Yang W, Yue DT (2010): Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin. Nature, pp 968– 972. PMC3553577 20139964
  103. [114]Xia XM, Fakler B, Rivard A, Wayman G, Johnson-Pais T, Keen JE, (1998): Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395: 503– 507. 9774106
  104. [115]Zhong L, Brown J, Kramer A, Kaleka K, Petersen A, Krueger JN, (2015): Increased prefrontal cortex neurogranin enhances plasticity and extinction learning. J Neurosci 35: 7503– 7508. 25972176 PMC4429154

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Authors
Hwang, H., Szucs, M. J., Ding, L. J., Allen, A., Ren, X., Haensgen, H., Gao, F., Rhim, H., Andrade, A., Pan, J. Q., Carr, S. A., Ahmad, R., & Xu, W.
Affiliations
  • Korean Association Of Science and Technology Studies (KR)
  • Broad Institute (US)
  • Massachusetts Institute of Technology (US)
  • Korea Institute of Science and Technology (KR)
  • University of New Hampshire (US)
Corresponding author
  • Hwang, Hongik
  • Xu, Weifeng
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2021-02
Volume
89
Issue
3
Pages
256-269
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2020.07.014
PMC
PMC9258036
OpenAlex
W3045942095
Cited by
49
References
11
Citations by year
2026: 11 · 2025: 10 · 2024: 9 · 2023: 6 · 2022: 9 · 2021: 2 · 2020: 1 · 2019: 1
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Research Foundation of Korea
  • National Institute of Mental Health
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
neurogranin, schizophrenia, synaptic plasticity, long-term potentiation, calmodulin, calcineurin, postsynaptic density proteins, hippocampus, autism-related genes, postsynaptic signaling
MeSH terms
Animals, Calmodulin, Hippocampus, Humans, Neuronal Plasticity, Schizophrenia, Synapses, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Mice, Neurogranin

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