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Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

Abstract

CACNA1C, encoding the Cav1.2 subunit of L-type Ca2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Cav1.2 channels play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Cav1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Cav1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.

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References

  1. 1

    Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM et al. CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol 2012; 99: 1–14.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Consortium C-DGotPG. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 2013; 381: 1371–1379.

    Article  CAS  Google Scholar 

  3. 3

    Heyes S, Pratt WS, Rees E, Dahimene S, Ferron L, Owen MJ et al. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Prog Neurobiol 2015; 134: 36–54.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 2010; 15: 1016–1022.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Li J, Zhao L, You Y, Lu T, Jia M, Yu H et al. Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism. PLoS ONE 2015; 10: e0133247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Network, Pathway Analysis Subgroup of Psychiatric Genomics C. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci 2015; 18: 199–209.

    Article  CAS  Google Scholar 

  8. 8

    Simms BA, Zamponi GW . Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 2014; 82: 24–45.

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 2011; 17: 1657–1662.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Zamponi GW, Striessnig J, Koschak A, Dolphin AC . The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 2015; 67: 821–870.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Kabir ZD, Lee AS, Rajadhyaksha AM . L-type Ca channels in mood, cognition and addiction: Integrating human and rodent studies with a focus on behavioural endophenotypes. J Physiol 2016; 594: 5823–5837.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Miyoshi M, Morimura Y . Clinical manifestations of neuropsychiatric disorders. Neuropsychiatr Disord 2010; Part I: 1–14.

    Google Scholar 

  13. 13

    Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clayton NS et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 2012; 11: 141–168.

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Miller EK . The prefrontal cortex and cognitive control. Nat Rev Neurosci 2000; 1: 59–65.

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC . Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci 2014; 8: 230.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Wang F, McIntosh AM, He Y, Gelernter J, Blumberg HP . The association of genetic variation in CACNA1C with structure and function of a frontotemporal system. Bipolar Disord 2011; 13: 696–700.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Bicks LK, Koike H, Akbarian S, Morishita H . Prefrontal cortex and social cognition in mouse and man. Front Psychol 2015; 6: 1805.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gao R, Penzes P . Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med 2015; 15: 146–167.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Mullins C, Fishell G, Tsien RW . Unifying views of autism spectrum disorders: a consideration of autoregulatory feedback loops. Neuron 2016; 89: 1131–1156.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Nelson SB, Valakh V . Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 2015; 87: 684–698.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 2011; 477: 171–178.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Santini E, Huynh TN, MacAskill AF, Carter AG, Pierre P, Ruggero D et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 2013; 493: 411–415.

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 2013; 493: 371–377.

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Huynh TN, Shah M, Koo SY, Faraud KS, Santini E, Klann E . eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors. Neurobiol Dis 2015; 83: 67–74.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Buffington SA, Huang W, Costa-Mattioli M . Translational control in synaptic plasticity and cognitive dysfunction. Annu Rev Neurosci 2014; 37: 17–38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Roussos P, Mitchell AC, Voloudakis G, Fullard JF, Pothula VM, Tsang J et al. A role for noncoding variation in schizophrenia. Cell Rep 2014; 9: 1417–1429.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Gershon ES, Grennan K, Busnello J, Badner JA, Ovsiew F, Memon S et al. A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain. Mol Psychiatry 2014; 19: 890–894.

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Lee AS, Ra S, Rajadhyaksha AM, Britt JK, De Jesus-Cortes H, Gonzales KL et al. Forebrain elimination of cacna1c mediates anxiety-like behavior in mice. Mol Psychiatry 2012; 17: 1054–1055.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Inan M, Zhao M, Manuszak M, Karakaya C, Rajadhyaksha AM, Pickel VM et al. Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability. Neurobiol Dis 2016; 93: 35–46.

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 2006; 314: 140–143.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Detrait E, brohez C, Hanon E, De Ryck M . Automation of continuous spontaneous alternation to increase the thoughput for in vivo screening of cognitive enhancers. Optimization of the ethovision system for the Y-maze test in mice. Proceedings of Measuring Behavior, 7th International Conference on Methods and Techniques in Behavioral Research, Eindhoven, The Netherlands, 2010, pp 141–144.

  32. 32

    Vorhees CV, Williams MT . Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1: 848–858.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Che A, Girgenti MJ, LoTurco J . The dyslexia-associated gene DCDC2 is required for spike-timing precision in mouse neocortex. Biol Psychiatry 2014; 76: 387–396.

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Schmidt EK, Clavarino G, Ceppi M, Pierre P . SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods 2009; 6: 275–277.

    CAS  Article  Google Scholar 

  35. 35

    Tropea TF, Kabir ZD, Kaur G, Rajadhyaksha AM, Kosofsky BE . Enhanced dopamine D1 and BDNF signaling in the adult dorsal striatum but not nucleus accumbens of prenatal cocaine treated mice. Front Psychiatry 2011; 2: 67.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Kabir ZD, Katzman AC, Kosofsky BE . Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero. PLoS ONE 2013; 8: e84165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2013; 2: e00498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Di Biase V, Obermair GJ, Szabo Z, Altier C, Sanguesa J, Bourinet E et al. Stable membrane expression of postsynaptic CaV1.2 calcium channel clusters is independent of interactions with AKAP79/150 and PDZ proteins. J Neurosci 2008; 28: 13845–13855.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Lee AS, De Jesus-Cortes H, Kabir ZD, Knobbe W, Orr M, Burgdorf C et al. The neuropsychiatric disease-associated gene cacna1c mediates survival of young hippocampal neurons. eNeuro 2016; 3: ENEURO.0006-16.2016.

  40. 40

    Kempermann G, Krebs J, Fabel K . The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatry 2008; 21: 290–295.

    Article  PubMed  Google Scholar 

  41. 41

    Allsop SA, Vander Weele CM, Wichmann R, Tye KM . Optogenetic insights on the relationship between anxiety-related behaviors and social deficits. Front Behav Neurosci 2014; 8: 241.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Silverman JL, Yang M, Lord C, Crawley JN . Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 2010; 11: 490–502.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Stemmelin J, Cohen C, Terranova JP, Lopez-Grancha M, Pichat P, Bergis O et al. Stimulation of the beta3-Adrenoceptor as a novel treatment strategy for anxiety and depressive disorders. Neuropsychopharmacology 2008; 33: 574–587.

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Hoffman KL . Modeling neuropsychiatric disorders in laboratory animals, 2016, ISBN: 978-0-08-100099-1.

    Chapter  Google Scholar 

  45. 45

    Indovina I, Robbins TW, Nunez-Elizalde AO, Dunn BD, Bishop SJ . Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans. Neuron 2011; 69: 563–571.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Sartori SB, Hauschild M, Bunck M, Gaburro S, Landgraf R, Singewald N . Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions. PLoS ONE 2011; 6: e16849.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Robinson OJ, Vytal K, Cornwell BR, Grillon C . The impact of anxiety upon cognition: perspectives from human threat of shock studies. Front Hum Neurosci 2013; 7: 203.

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Lara AH, Wallis JD . The Role of Prefrontal Cortex in Working Memory: A Mini Review. Front Syst Neurosci 2015; 9: 173.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Darnell JC, Klann E . The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci 2013; 16: 1530–1536.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Costa-Mattioli M, Monteggia LM . mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 2013; 16: 1537–1543.

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Autry AE, Monteggia LM . Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64: 238–258.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L et al. Autism-like deficits in shank3-deficient mice are rescued by targeting actin regulators. Cell Rep 2015; 11: 1400–1413.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 2014; 83: 1131–1143.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Samaco RC, McGraw CM, Ward CS, Sun Y, Neul JL, Zoghbi HY . Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum Mol Genet 2013; 22: 96–109.

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW . Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J Neurosci 2014; 34: 2754–2763.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Sceniak MP, Lang M, Enomoto AC, Howell CJ, Hermes DJ, Katz DM . Mechanisms of functional hypoconnectivity in the medial prefrontal cortex of Mecp2 null mice. Cereb Cortex 2016; 26: 1938–1956.

    Article  PubMed  Google Scholar 

  57. 57

    Bigos KL, Mattay VS, Callicott JH, Straub RE, Vakkalanka R, Kolachana B et al. Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch Gen Psychiatry 2010; 67: 939–945.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Yoshimizu T, Pan JQ, Mungenast AE, Madison JM, Su S, Ketterman J et al. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol Psychiatry 2015; 20: 162–169.

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Eckart N, Song Q, Yang R, Wang R, Zhu H, McCallion AS et al. Functional Characterization of Schizophrenia-Associated Variation in CACNA1C. PLoS ONE 2016; 11: e0157086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW et al. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci USA 2011; 108: 15432–15437.

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Roussos P, Giakoumaki SG, Georgakopoulos A, Robakis NK, Bitsios P . The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males. Bipolar Disord 2011; 13: 250–259.

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Dietsche B, Backes H, Laneri D, Weikert T, Witt SH, Rietschel M et al. The impact of a CACNA1C gene polymorphism on learning and hippocampal formation in healthy individuals: a diffusion tensor imaging study. Neuroimage 2014; 89: 256–261.

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Erk S, Meyer-Lindenberg A, Linden DE, Lancaster T, Mohnke S, Grimm O et al. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. Neuroimage 2014; 94: 147–154.

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Erk S, Meyer-Lindenberg A, Schnell K, Opitz von Boberfeld C, Esslinger C, Kirsch P et al. Brain function in carriers of a genome-wide supported bipolar disorder variant. Arch Gen Psychiatry 2010; 67: 803–811.

    Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Hori H, Yamamoto N, Fujii T, Teraishi T, Sasayama D, Matsuo J et al. Effects of the CACNA1C risk allele on neurocognition in patients with schizophrenia and healthy individuals. Sci Rep 2012; 2: 634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Murray AJ, Woloszynowska-Fraser MU, Ansel-Bollepalli L, Cole KL, Foggetti A, Crouch B et al. Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility. Sci Rep 2015; 5: 16778.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Koester SE, Insel TR . Understanding how non-coding genomic polymorphisms affect gene expression. Mol Psychiatry 2016; 21: 448–449.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Calhoon GG, Tye KM . Resolving the neural circuits of anxiety. Nat Neurosci 2015; 18: 1394–1404.

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Liang J, Xu W, Hsu YT, Yee AX, Chen L, Sudhof TC . Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments. Mol Psychiatry 2015; 20: 850–859.

    CAS  Article  PubMed  Google Scholar 

  70. 70

    Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB et al. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission. Nature 2012; 489: 385–390.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Zimmerman HR, Beckelman B, Yang W, Ma T . Interactions between the eIF2a and mTORC1 signaling pathways. Program No 12602 2016 Neuroscience Meeting Planner. Society for Neuroscience, Online: San Diego, CA, USA, 2016.

    Google Scholar 

  72. 72

    Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet 2011; 20: 1182–1196.

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K et al. Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc Natl Acad Sci USA 2009; 106: 4882–4887.

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Gemelli T, Berton O, Nelson ED, Perrotti LI, Jaenisch R, Monteggia LM . Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol Psychiatry 2006; 59: 468–476.

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Nicolini C, Ahn Y, Michalski B, Rho JM, Fahnestock M . Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid. Acta Neuropathol Commun 2015; 3: 3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R, Cuello C et al. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 2007; 129: 195–206.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Costa-Mattioli M, Gobert D, Harding H, Herdy B, Azzi M, Bruno M et al. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 2005; 436: 1166–1173.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Trinh MA, Ma T, Kaphzan H, Bhattacharya A, Antion MD, Cavener DR et al. The eIF2alpha kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression. Learn Mem 2014; 21: 298–304.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Trinh MA, Kaphzan H, Wek RC, Pierre P, Cavener DR, Klann E . Brain-specific disruption of the eIF2alpha kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep 2012; 1: 676–688.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Sidrauski C, McGeachy AM, Ingolia NT, Walter P . The small molecule ISRIB reverses the effects of eIF2alpha phosphorylation on translation and stress granule assembly. eLife 2015; 4; doi: 10.7554/eLife.05033.

  81. 81

    Dolmetsch RE, Pajvani U, Fife K, Spotts JM, Greenberg ME . Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 2001; 294: 333–339.

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Klann E, Dever TE . Biochemical mechanisms for translational regulation in synaptic plasticity. Nat Rev Neurosci 2004; 5: 931–942.

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Sutton MA, Schuman EM . Dendritic protein synthesis, synaptic plasticity, and memory. Cell 2006; 127: 49–58.

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Pasini S, Corona C, Liu J, Greene LA, Shelanski ML . Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory. Cell Rep 2015; 11: 183–191.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Nadif Kasri N, Nakano-Kobayashi A, Van Aelst L . Rapid synthesis of the X-linked mental retardation protein OPHN1 mediates mGluR-dependent LTD through interaction with the endocytic machinery. Neuron 2011; 72: 300–315.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Di Prisco GV, Huang W, Buffington SA, Hsu CC, Bonnen PE, Placzek AN et al. Translational control of mGluR-dependent long-term depression and object-place learning by eIF2alpha. Nat Neurosci 2014; 17: 1073–1082.

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Rudell JB, Rechs AJ, Kelman TJ, Ross-Inta CM, Hao S, Gietzen DW . The anterior piriform cortex is sufficient for detecting depletion of an indispensable amino acid, showing independent cortical sensory function. J Neurosci 2011; 31: 1583–1590.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Zheng F, Zhou X, Luo Y, Xiao H, Wayman G, Wang H . Regulation of brain-derived neurotrophic factor exon IV transcription through calcium responsive elements in cortical neurons. PLoS ONE 2011; 6: e28441.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Mounir Z, Krishnamoorthy JL, Wang S, Papadopoulou B, Campbell S, Muller WJ et al. Akt determines cell fate through inhibition of the PERK-eIF2alpha phosphorylation pathway. Sci Signal 2011; 4: ra62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by The Hartwell Foundation (AMR), the Weill Cornell Autism Research Program (AMR), the Weill Cornell Medicine Postdoctoral Fellowship (ZDK), the National Institutes of Health (5R01DA029122 to AMR; 5 R00 MH095825 05 and 1 R01 MH110553 01 to NVDMG), Leon Levy Foundation (NVDMG), and Citizens United for Research in Epilepsy (CURE; NVDMG). We thank Dr Jacqueline Crawley for technical assistance with establishing the social interaction behavioral apparatus and procedure in our laboratory. We thank Drs Eric Klann, Aditi Bhattacharya, Alexandra Cohen and Anni Lee for technical assistance with establishing the water-based Y-maze behavioral paradigm in our laboratory. We thank Dr Andrew Pieper for critical reading of the manuscript and Dr Héctor De Jesús-Cortés for his comments on the figures.

Author contributions

ZDK and AMR contributed to the experimental design, data interpretation and wrote the paper. AC and NVDMG performed electrophysiological experiments and analyzed data. ZDK performed stereotaxic surgeries and analyzed data. ZDK and DKF conducted molecular and behavioral experiments. BR conducted molecular experiments. RCR and MB conducted behavioral experiments. MJG conducted electron microscopy experiments. All authors discussed and commented on the manuscript.

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Correspondence to A M Rajadhyaksha.

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Kabir, Z., Che, A., Fischer, D. et al. Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α. Mol Psychiatry 22, 1096–1109 (2017). https://doi.org/10.1038/mp.2017.124

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