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Identifying dysfunctional cell types and circuits in animal models for psychiatric disorders with calcium imaging

Neuropsychopharmacology (2024)Cite this article

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A Correction to this article was published on 09 September 2024

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Abstract

A central goal of neuroscience is to understand how the brain transforms external stimuli and internal bodily signals into patterns of activity that underlie cognition, emotional states, and behavior. Understanding how these patterns of activity may be disrupted in mental illness is crucial for developing novel therapeutics. It is well appreciated that psychiatric disorders are complex, circuit-based disorders that arise from dysfunctional activity patterns generated in discrete cell types and their connections. Recent advances in large-scale, cell-type specific calcium imaging approaches have shed new light on the cellular, circuit, and network-level dysfunction in animal models for psychiatric disorders. Here, we highlight a series of recent findings over the last ~10 years from in vivo calcium imaging studies that show how aberrant patterns of activity in discrete cell types and circuits may underlie behavioral deficits in animal models for several psychiatric disorders, including depression, anxiety, autism spectrum disorders, and schizophrenia. These advances in calcium imaging in pre-clinical models demonstrate the power of cell-type-specific imaging tools in understanding the underlying dysfunction in cell types, activity patterns, and neural circuits that may contribute to disease and provide new blueprints for developing more targeted therapeutics and treatment strategies.

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Fig. 1: Workflow of in vivo imaging of rodents during behavior.
Fig. 2: Future directions.

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References

  1. Xia F, Kheirbek MA. Circuit-based biomarkers for mood and anxiety disorders. Trends Neurosci. 2020;43:902–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhou ZC, Gordon-Fennell A, Piantadosi SC, Ji N, Smith SL, Bruchas MR, Stuber GD. Deep-brain optical recording of neural dynamics during behavior. Neuron. 2023;111:3716–38.

    CAS  PubMed  Google Scholar 

  3. Bi X, Beck C, Gong Y. Genetically encoded fluorescent indicators for imaging brain chemistry. Biosensors. 2021;11:116.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lin MZ, Schnitzer MJ. Genetically encoded indicators of neuronal activity. Nat Neurosci. 2016;19:1142–53.

    PubMed  PubMed Central  Google Scholar 

  5. Day‐Cooney J, Dalangin R, Zhong H, Mao T. Genetically encoded fluorescent sensors for imaging neuronal dynamics in vivo. J Neurochem. 2023;164:284–308.

    PubMed  Google Scholar 

  6. Grienberger C, Konnerth A. Imaging calcium in neurons. Neuron. 2012;73:862–85.

    CAS  PubMed  Google Scholar 

  7. Garaschuk O, Milos RI, Grienberger C, Marandi N, Adelsberger H, Konnerth A. Optical monitoring of brain function in vivo: from neurons to networks. Pflüg Arch - Eur J Physiol. 2006;453:385–96.

    CAS  Google Scholar 

  8. Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000;1:11–21.

    CAS  PubMed  Google Scholar 

  9. Wu Z, Lin D, Li Y. Pushing the frontiers: tools for monitoring neurotransmitters and neuromodulators. Nat Rev Neurosci. 2022;23:257–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang H, Qian T, Zhao Y, Zhuo Y, Wu C, Osakada T, et al. A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors. Science. 2023;382:eabq8173.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Willmore L, Cameron C, Yang J, Witten IB, Falkner AL. Behavioural and dopaminergic signatures of resilience. Nature. 2022;611:124–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Steinmetz NA, Aydin C, Lebedeva A, Okun M, Pachitariu M, Bauza M, et al. Neuropixels 2.0: a miniaturized high-density probe for stable, long-term brain recordings. Science. 2021;372:eabf4588.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Jun JJ, Steinmetz NA, Siegle JH, Denman DJ, Bauza M, Barbarits B, et al. Fully integrated silicon probes for high-density recording of neural activity. Nature. 2017;551:232–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zong W, Obenhaus HA, Skytøen ER, Eneqvist H, de Jong NL, Vale R, et al. Large-scale two-photon calcium imaging in freely moving mice. Cell. 2022;185:1240–1256.e30.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fenno LE, Ramakrishnan C, Kim YS, Evans KE, Lo M, Vesuna S, et al. Comprehensive dual- and triple-feature intersectional single-vector delivery of diverse functional payloads to cells of behaving mammals. Neuron. 2020;107:836–853.e11.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Fenno LE, Mattis J, Ramakrishnan C, Hyun M, Lee SY, He M, et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat Methods. 2014;11:763–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Padilla-Coreano N, Canetta S, Mikofsky RM, Alway E, Passecker J, Myroshnychenko MV, et al. Hippocampal-prefrontal theta transmission regulates avoidance behavior. Neuron. 2019;104:601–610.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Broussard GJ, Liang Y, Fridman M, Unger EK, Meng G, Xiao X, et al. In vivo measurement of afferent activity with axon-specific calcium imaging. Nat Neurosci. 2018;21:1272–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen Y, Jang H, Spratt P, Kosar S, Taylor DE, Essner RA, et al. Soma-targeted imaging of neural circuits by ribosome tethering. Neuron. 2020;107:454–469.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A, et al. Natural neural projection dynamics underlying social behavior. Cell. 2014;157:1535–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature. 2013;494:238–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tecuapetla F, Matias S, Dugue GP, Mainen ZF, Costa RM. Balanced activity in basal ganglia projection pathways is critical for contraversive movements. Nat Commun. 2014;5:4315.

    CAS  PubMed  Google Scholar 

  23. Allen WE, Kauvar IV, Chen MZ, Richman EB, Yang SJ, Chan K, et al. Global representations of goal-directed behavior in distinct cell types of mouse neocortex. Neuron. 2017;94:891–907.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Couto J, Musall S, Sun XR, Khanal A, Gluf S, Saxena S, et al. Chronic, cortex-wide imaging of specific cell populations during behavior. Nat Protoc. 2021;16:3241–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Makino H, Ren C, Liu H, Kim AN, Kondapaneni N, Liu X, et al. Transformation of cortex-wide emergent properties during motor learning. Neuron. 2017;94:880–890.e8.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ren C, Komiyama T. Characterizing cortex-wide dynamics with wide-field calcium imaging. J Neurosci. 2021;41:4160–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang L, Liang B, Barbera G, Hawes S, Zhang Y, Stump K, et al. Miniscope GRIN lens system for calcium imaging of neuronal activity from deep brain structures in behaving animals. Curr Protoc Neurosci. 2019;86:e56.

    PubMed  Google Scholar 

  28. Kahan A, Greenbaum A, Jang MJ, Robinson JE, Cho JR, Chen X, et al. Light-guided sectioning for precise in situ localization and tissue interface analysis for brain-implanted optical fibers and GRIN lenses. Cell Rep. 2021;36:109744.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang W, Carrillo-Reid L, Bando Y, Peterka DS, Yuste R. Simultaneous two-photon imaging and two-photon optogenetics of cortical circuits in three dimensions. eLife. 2018;7:e32671.

    PubMed  PubMed Central  Google Scholar 

  30. Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Biane JS, Ladow MA, Stefanini F, Boddu SP, Fan A, Hassan S, et al. Neural dynamics underlying associative learning in the dorsal and ventral hippocampus. Nat Neurosci. 2023;26:798–809.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Andrasfalvy BK, Zemelman BV, Tang J, Vaziri A. Two-photon single-cell optogenetic control of neuronal activity by sculpted light. Proc Natl Acad Sci. 2010;107:11981–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Piantadosi SC, Zhou ZC, Pizzano C, Pedersen CE, Nguyen TK, Thai S, et al. Holographic stimulation of opposing amygdala ensembles bidirectionally modulates valence-specific behavior via mutual inhibition. Neuron. 2024;112:593–610.e5.

    CAS  PubMed  Google Scholar 

  34. Zhdanava M, Pilon D, Ghelerter I, Chow W, Joshi K, Lefebvre P, Sheehan JJ. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82:20m13699.

    PubMed  Google Scholar 

  35. Greenberg P, Chitnis A, Louie D, Suthoff E, Chen SY, Maitland J, et al. The economic burden of adults with major depressive disorder in the United States (2019). Adv Ther. 2023;40:4460–79.

    PubMed  PubMed Central  Google Scholar 

  36. Atrooz F, Alkadhi KA, Salim S. Understanding stress: Insights from rodent models. Curr Res Neurobiol. 2021;2:100013.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Planchez B, Surget A, Belzung C. Animal models of major depression: drawbacks and challenges. J Neural Transm. 2019;126:1383–408.

    CAS  PubMed  Google Scholar 

  38. Samuels BA, Leonardo ED, Gadient R, Williams A, Zhou J, David DJ, et al. Modeling treatment-resistant depression. Neuropharmacology. 2011;61:408–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kolasa M, Faron-Górecka A. Preclinical models of treatment-resistant depression: challenges and perspectives. Pharmacol Rep. 2023;75:1326–40.

    PubMed  PubMed Central  Google Scholar 

  40. Pilmeyer J, Huijbers W, Lamerichs R, Jansen J, Breeuwer M, Zinger S. Functional MRI in major depressive disorder: a review of findings, limitations, and future prospects. J Neuroimaging. 2022;32:582–95.

    PubMed  PubMed Central  Google Scholar 

  41. Liu RT, Alloy LB. Stress generation in depression: a systematic review of the empirical literature and recommendations for future study. Clin Psychol Rev. 2010;30:582–93.

    PubMed  PubMed Central  Google Scholar 

  42. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298:1685–7.

    CAS  PubMed  Google Scholar 

  43. Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

    CAS  PubMed  Google Scholar 

  45. Qi G, Zhang P, Li T, Li M, Zhang Q, He F, et al. NAc-VTA circuit underlies emotional stress-induced anxiety-like behavior in the three-chamber vicarious social defeat stress mouse model. Nat Commun. 2022;13:577.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Muir J, Lorsch ZS, Ramakrishnan C, Deisseroth K, Nestler EJ, Calipari ES, Bagot RC. In vivo fiber photometry reveals signature of future stress susceptibility in nucleus accumbens. Neuropsychopharmacology. 2018;43:255–63.

    CAS  PubMed  Google Scholar 

  47. Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gergues MM, Han KJ, Choi HS, Brown B, Clausing KJ, Turner VS, et al. Circuit and molecular architecture of a ventral hippocampal network. Nat Neurosci. 2020;23:1444–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Li L, Durand-de Cuttoli R, Aubry AV, Burnett CJ, Cathomas F, Parise LF, et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature. 2023;613:696–703.

    CAS  PubMed  Google Scholar 

  50. Li, F et al. Mediodorsal thalamus projection to medial prefrontal cortical mediates social defeat stress-induced depression-like behaviors. Neuropsychopharmacology. 2024. https://doi.org/10.1038/s41386-024-01829-y.

  51. Haynes SE, Lacagnina A, Seong HS, Afzal M, Morel C, et al. CRF neurons establish resilience via stress-history dependent BNST modulation. 2022. http://biorxiv.org/lookup/doi/10.1101/2022.08.31.505596, https://doi.org/10.1101/2022.08.31.505596.

  52. Fetcho RN, Parekh PK, Chou J, Kenwood M, Chalençon L, Estrin DJ, et al. A stress-sensitive frontostriatal circuit supporting effortful reward-seeking behavior. Neuron. 2024;112:473–487.e4.

    CAS  PubMed  Google Scholar 

  53. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.

    CAS  PubMed  Google Scholar 

  54. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012;37:1526–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shao L-X, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, Kwan AC. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021;109:2535–2544.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Gao Y, Gao D, Zhang H, Zheng D, Du J, Yuan C, et al. BLA DBS improves anxiety and fear by correcting weakened synaptic transmission from BLA to adBNST and CeL in a mouse model of foot shock. Cell Rep. 2024;43:113766.

    CAS  PubMed  Google Scholar 

  59. Penninx BW, Pine DS, Holmes EA, Reif A. Anxiety disorders. Lancet. 2021;397:914–27.

    PubMed  PubMed Central  Google Scholar 

  60. Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A. Neurobiological links between stress and anxiety. Neurobiol Stress. 2019;11:100191.

    PubMed  PubMed Central  Google Scholar 

  61. Samuels BA, Hen R. Novelty-Suppressed Feeding in the Mouse. Mood and anxiety related phenotypes in mice: characterization using behavioral tests, Volume II. Totowa, NJ: Humana Press; 2011. pp.107–121

  62. Calhoon GG, Tye KM. Resolving the neural circuits of anxiety. Nat Neurosci. 2015;18:1394–404.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Jimenez JC, Su K, Goldberg AR, Luna VM, Biane JS, Ordek G, et al. Anxiety cells in a hippocampal-hypothalamic circuit. Neuron. 2018;97:670–683.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lim SC, Fusi S, Hen R. Ventral CA1 population codes for anxiety. 2023. http://biorxiv.org/lookup/doi/10.1101/2023.09.25.559358, https://doi.org/10.1101/2023.09.25.559358.

  65. Turner VS, O’Sullivan RO, Kheirbek MA. Linking external stimuli with internal drives: a role for the ventral hippocampus. Curr Opin Neurobiol. 2022;76:102590.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pi G, Gao D, Wu D, Wang Y, Lei H, Zeng W, et al. Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect. Nat Commun. 2020;11:183.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sánchez-Bellot C, AlSubaie R, Mishchanchuk K, Wee RWS, MacAskill AF. Two opposing hippocampus to prefrontal cortex pathways for the control of approach and avoidance behaviour. Nat Commun. 2022;13:339.

    PubMed  PubMed Central  Google Scholar 

  68. Gehrlach DA, Dolensek N, Klein AS, Roy Chowdhury R, Matthys A, Junghänel M, et al. Aversive state processing in the posterior insular cortex. Nat Neurosci. 2019;22:1424–37.

    CAS  PubMed  Google Scholar 

  69. Fitzgerald JM, DiGangi JA, Phan KL. Functional neuroanatomy of emotion and its regulation in PTSD. Harv Rev Psychiatry. 2018;26:116–28.

    PubMed  PubMed Central  Google Scholar 

  70. Kunimatsu A, Yasaka K, Akai H, Kunimatsu N, Abe O. MRI findings in posttraumatic stress disorder. J Magn Reson Imaging. 2020;52:380–96.

    PubMed  Google Scholar 

  71. Taschereau-Dumouchel V, Michel M, Lau H, Hofmann SG, LeDoux JE. Putting the “mental” back in “mental disorders”: a perspective from research on fear and anxiety. Mol Psychiatry. 2022;27:1322–30.

    PubMed  PubMed Central  Google Scholar 

  72. LeDoux J, Daw ND. Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour. Nat Rev Neurosci. 2018;19:269–82.

    CAS  PubMed  Google Scholar 

  73. LeDoux JE, Brown R. A higher-order theory of emotional consciousness. Proc Natl Acad Sci. 2017;114:E2016–E2025.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gründemann J, Bitterman Y, Lu T, Krabbe S, Grewe BF, Schnitzer MJ, Lüthi A. Amygdala ensembles encode behavioral states. Science. 2019;364:eaav8736.

    PubMed  Google Scholar 

  75. Hagihara KM, Bukalo O, Zeller M, Aksoy-Aksel A, Karalis N, Limoges A, et al. Intercalated amygdala clusters orchestrate a switch in fear state. Nature. 2021;594:403–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Hallock HL, Quillian HM, Maynard KR, Mai Y, Chen HY, Hamersky GR, et al. Molecularly defined hippocampal inputs regulate population dynamics in the prelimbic cortex to suppress context fear memory retrieval. Biol Psychiatry. 2020;88:554–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zaki Y, Mau W, Cincotta C, Monasterio A, Odom E, Doucette E, et al. Hippocampus and amygdala fear memory engrams re-emerge after contextual fear relapse. Neuropsychopharmacology. 2022;47:1992–2001.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kirkby LA, Luongo FJ, Lee MB, Nahum M, Van Vleet TM, Rao VR, et al. An amygdala-hippocampus subnetwork that encodes variation in human mood. Cell. 2018;175:1688–1700.e14.

    CAS  PubMed  Google Scholar 

  79. Jackson AD, Cohen JL, Phensy AJ, Chang EF, Dawes HE, Sohal VS, et al. Amygdala-hippocampus somatostatin interneuron beta-synchrony underlies a cross-species biomarker of emotional state. Neuron. 2024; S0896627323009765. https://doi.org/10.1016/j.neuron.2023.12.017.

  80. Chamberlain BL, Ahmari SE. Animal Models for OCD Research. Curr Top Behav Neurosci. 2021;49:55–96.

  81. Ahmari SE, Spellman T, Douglass NL, Kheirbek MA, Simpson HB, Deisseroth K, et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science. 2013;340:1234–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature. 2007;448:894–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. St. Laurent R, Kusche KM, Kreitzer AC, Malenka RC. Intercalated amygdala dysfunction drives extinction deficits in the Sapap3 mouse model of obsessive-compulsive disorder. 2024. https://www.biorxiv.org/content/10.1101/2024.02.12.578709v1#:~:text=Results%20We%20find%20impaired%20neural,by%20ITCd%20neural%20activity.

  84. Manning EE, Geramita MA, Piantadosi SC, Pierson JL, Ahmari SE. Distinct patterns of abnormal lateral orbitofrontal cortex activity during compulsive grooming and reversal learning normalize after fluoxetine. Biol Psychiatry. 2023;93:989–99.

    CAS  PubMed  Google Scholar 

  85. Lai M-C, Lombardo M V, Baron-Cohen S. Autism. Lancet. 2014;383:896–910.

    PubMed  Google Scholar 

  86. Terashima H, Minatohara K, Maruoka H, Okabe S. Imaging neural circuit pathology of autism spectrum disorders: autism-associated genes, animal models and the application of in vivo two-photon imaging. Microscopy. 2022;71:i81–i99.

    CAS  PubMed  Google Scholar 

  87. Havdahl A, Niarchou M, Starnawska A, Uddin M, van der Merwe C, Warrier V. Genetic contributions to autism spectrum disorder. Psychol Med. 2021;51:2260–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Shimizu A, Asakawa S, Sasaki T, Yamazaki S, Yamagata H, Kudoh J, et al. A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains: a candidate gene for benign adult familial myoclonic epilepsy on human chromosome 8q23.3–q24.1. Biochem Biophys Res Commun. 2003;309:143–54.

    CAS  PubMed  Google Scholar 

  89. Wu J, Yu P, Jin X, Xu X, Li J, Li Z, et al. Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing. J Genet Genomics. 2018;45:527–38.

    CAS  PubMed  Google Scholar 

  90. Bork P, Beckmann G. The CUB domain: a widespread module in developmentally regulated proteins. J Mol Biol. 1993;231:539–45.

    CAS  PubMed  Google Scholar 

  91. Holmquist E, Okroj M, Nodin B, Jirström K, Blom AM. Sushi domain-containing protein 4 (SUSD4) inhibits complement by disrupting the formation of the classical C3 convertase. FASEB J. 2013;27:2355–66.

    CAS  PubMed  Google Scholar 

  92. Song W, Li Q, Wang T, Li Y, Fan T, Zhang J, et al. Putative complement control protein CSMD3 dysfunction impairs synaptogenesis and induces neurodevelopmental disorders. Brain Behav Immun. 2022;102:237–50.

    CAS  PubMed  Google Scholar 

  93. Oeschger FM, Wang WZ, Lee S, García-Moreno F, Goffinet AM, Arbonés ML, et al. Gene expression analysis of the embryonic subplate. Cereb Cortex. 2012;22:1343–59.

    PubMed  Google Scholar 

  94. Xi K, Cai SQ, Yan HF, Tian Y, Cai J, Yang XM, et al. CSMD3 deficiency leads to motor impairments and autism-like behaviors via dysfunction of cerebellar purkinje cells in mice. J Neurosci. 2023;43:3949–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess. 2003;7:1–106.

  96. Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet. 2008;16:666–72.

    CAS  PubMed  Google Scholar 

  97. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991;66:817–22.

    CAS  PubMed  Google Scholar 

  98. Bassell GJ, Warren ST. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60:201–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Gonçalves JT, Anstey JE, Golshani P, Portera-Cailliau C. Circuit level defects in the developing neocortex of Fragile X mice. Nat Neurosci. 2013;16:903–9.

  100. Golshani P, Gonçalves JT, Khoshkhoo S, Mostany R, Smirnakis S, Portera-Cailliau C. Internally mediated developmental desynchronization of neocortical network activity. J Neurosci. 2009;29:10890–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rochefort NL, Garaschuk O, Milos RI, Narushima M, Marandi N, Pichler B, et al. Sparsification of neuronal activity in the visual cortex at eye-opening. Proc Natl Acad Sci USA. 2009;106:15049–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Buckley AW, Rodriguez AJ, Jennison K, Buckley J, Thurm A, Sato S, et al. Rapid eye movement sleep percentage in children with autism compared with children with developmental delay and typical development. Arch Pediatr Adolesc Med. 2010;164:1032–7.

    PubMed  PubMed Central  Google Scholar 

  103. Elia M, Ferri R, Musumeci SA, Del Gracco S, Bottitta M, Scuderi C, et al. Sleep in subjects with autistic disorder: a neurophysiological and psychological study. Brain Dev. 2000;22:88–92.

    CAS  PubMed  Google Scholar 

  104. He CX, Cantu DA, Mantri SS, Zeiger WA, Goel A, Portera-Cailliau C. Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knock-out mouse model of autism. J Neurosci J Soc Neurosci. 2017;37:6475–87.

    CAS  Google Scholar 

  105. Tomchek SD, Dunn W. Sensory processing in children with and without autism: a comparative study using the short sensory profile. Am J Occup Ther. 2007;61:190–200.

    PubMed  Google Scholar 

  106. Butler MG, Allen GA, Haynes JL, Singh DN, Watson MS, Breg WR. Anthropometric comparison of mentally retarded males with and without the fragile X syndrome. Am J Med Genet. 1991;38:260–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Butler MG, Mangrum T, Gupta R, Singh DN. A 15-item checklist for screening mentally retarded males for the fragile X syndrome. Clin Genet. 1991;39:347–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Goel A, Cantu DA, Guilfoyle J, Chaudhari GR, Newadkar A, Todisco B, et al. Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. Nat Neurosci. 2018;21:1404–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Robertson CE, Baron-Cohen S. Sensory perception in autism. Nat Rev Neurosci. 2017;18:671–84.

  110. Jiang Y, Ehlers MD. Modeling autism by SHANK gene mutations in mice. Neuron. 2013;78:8–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39:25–27.

    CAS  PubMed  Google Scholar 

  112. Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism. 2010;1:15.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Yang M, Bozdagi O, Scattoni ML, Wöhr M, Roullet FI, Katz AM, et al. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci J Soc Neurosci. 2012;32:6525–41.

    CAS  Google Scholar 

  114. Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC, et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011;20:3093–108.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472:437–42.

    PubMed  PubMed Central  Google Scholar 

  116. Chen Q, Deister CA, Gao X, Guo B, Lynn-Jones T, Chen N, et al. Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD. Nat Neurosci. 2020;23:520–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang D, Yu B, Liu J, Jiang W, Xie T, Zhang R, et al. Altered visual cortical processing in a mouse model of MECP2 duplication syndrome. Sci Rep. 2017;7:6468.

    PubMed  PubMed Central  Google Scholar 

  118. Ortiz-Cruz CA, Marquez EJ, Linares-García CI, Perera-Murcia GR, Ramiro-Cortés Y. Haploinsufficiency of Shank3 increases the orientation selectivity of V1 neurons. Sci Rep. 2022;12:22230.

    PubMed  PubMed Central  Google Scholar 

  119. Nakabayashi K, Scherer SW. The human contactin-associated protein-like 2 gene (CNTNAP2) spans over 2 Mb of DNA at chromosome 7q35. Genomics. 2001;73:108–12.

    CAS  PubMed  Google Scholar 

  120. Rodenas-Cuadrado P, Ho J, Vernes SC. Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet. 2014;22:171–8.

    CAS  PubMed  Google Scholar 

  121. Geramita MA, Wen JA, Rannals MD, Urban NN. Decreased amplitude and reliability of odor-evoked responses in two mouse models of autism. J Neurophysiol. 2020;123:1283–94.

    CAS  PubMed  Google Scholar 

  122. Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, et al. Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron. 1999;24:1037–47.

    CAS  PubMed  Google Scholar 

  123. Inda MC, DeFelipe J, Muñoz A. Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proc Natl Acad Sci USA. 2006;103:2920–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Duflocq A, Chareyre F, Giovannini M, Couraud F, Davenne M. Characterization of the axon initial segment (AIS) of motor neurons and identification of a para-AIS and a juxtapara-AIS, organized by protein 4.1B. BMC Biol. 2011;9:66.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Gordon A, Salomon D, Barak N, Pen Y, Tsoory M, Kimchi T, et al. Expression of Cntnap2 (Caspr2) in multiple levels of sensory systems. Mol Cell Neurosci. 2016;70:42–53.

    CAS  PubMed  Google Scholar 

  126. Frost NA, Haggart A, Sohal VS. Dynamic patterns of correlated activity in the prefrontal cortex encode information about social behavior. PLoS Biol. 2021;19:e3001235.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Resendez SL, Namboodiri V, Otis JM, Eckman L, Rodriguez-Romaguera J, Ung RL, et al. Social stimuli induce activation of oxytocin neurons within the paraventricular nucleus of the hypothalamus to promote social behavior in male mice. J Neurosci J Soc Neurosci. 2020;40:2282–95.

    CAS  Google Scholar 

  128. Selimbeyoglu A, Kim CK, Inoue M, Lee SY, Hong A, Kauvar I, et al. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci Transl Med. 2017;9:eaah6733.

    PubMed  PubMed Central  Google Scholar 

  129. Brumback AC, Ellwood IT, Kjaerby C, Iafrati J, Robinson S, Lee AT, et al. Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior. Mol Psychiatry. 2018;23:2078–89.

    CAS  PubMed  Google Scholar 

  130. Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophrenia: a reexamination. Arch Gen Psychiatry. 2005;62:247–53.

    PubMed  Google Scholar 

  131. Olfson M, Gerhard T, Huang C, Crystal S, Stroup TS. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry. 2015;72:1172–81.

    PubMed  Google Scholar 

  132. Velligan DI, Rao S. The epidemiology and global burden of schizophrenia. J Clin Psychiatry. 2023;84:MS21078COM5.

    PubMed  Google Scholar 

  133. Gandal MJ, Edgar JC, Klook K, Siegel SJ. Gamma synchrony: towards a translational biomarker for the treatment resistant symptoms of schizophrenia. Neuropharmacology. 2012;62:1504–18.

    CAS  PubMed  Google Scholar 

  134. Sohal VS. Neurobiology of schizophrenia. Curr Opin Neurobiol. 2024;84:102820.

    CAS  PubMed  Google Scholar 

  135. Kharawala S, Hastedt C, Podhorna J, Shukla H, Kappelhoff B, Harvey PD. The relationship between cognition and functioning in schizophrenia: a semi-systematic review. Schizophr Res Cogn. 2022;27:100217.

    PubMed  Google Scholar 

  136. Domino EF, Luby ED. Phencyclidine/schizophrenia: one view toward the past, the other to the future. Schizophr Bull. 2012;38:914–9.

    PubMed  PubMed Central  Google Scholar 

  137. Noda Y, Yamada K, Furukawa H, Nabeshima T. Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. Br J Pharmacol. 1995;116:2531–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Schmack K, Bosc M, Ott T, Sturgill JF, Kepecs A. Striatal dopamine mediates hallucination-like perception in mice. Science. 2021;372:eabf4740.

    CAS  PubMed  Google Scholar 

  139. Fénelon K, Xu B, Lai CS, Mukai J, Markx S, Stark KL, et al. The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion. J Neurosci. 2013;33:14825–39.

    PubMed  PubMed Central  Google Scholar 

  140. Zaremba JD, Diamantopoulou A, Danielson NB, Grosmark AD, Kaifosh PW, Bowler JC, et al. Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion. Nat Neurosci. 2017;20:1612–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Marissal T, Salazar RF, Bertollini C, Mutel S, De Roo M, Rodriguez I, et al. Restoring wild type-like CA1 network dynamics and behaviour during adulthood in a mouse model of schizophrenia. Nat Neurosci. 2018;21:1412–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Mesbah-Oskui L, Georgiou J, Roder JC. Hippocampal place cell and inhibitory neuron activity in disrupted-in-schizophrenia-1 mutant mice: implications for working memory deficits. NPJ Schizophr. 2015;1:1–7.

    Google Scholar 

  143. Mathis A, Mamidanna P, Cury KM, Abe T, Murthy VN, Mathis MW, et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat Neurosci. 2018;21:1281–9.

    CAS  PubMed  Google Scholar 

  144. Weinreb C, Pearl JE, Lin S, Osman MAM, Zhang L, Annapragada S, et al. Keypoint-MoSeq: parsing behavior by linking point tracking to pose dynamics. 2023. http://biorxiv.org/lookup/doi/10.1101/2023.03.16.532307, https://doi.org/10.1101/2023.03.16.532307.

  145. Pan S, Mayoral SR, Choi HS, Chan JR, Kheirbek MA. Preservation of a remote fear memory requires new myelin formation. Nat Neurosci. 2020;23:487–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Hughes EG, Orthmann-Murphy JL, Langseth AJ, Bergles DE. Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex. Nat Neurosci. 2018;21:696–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Bacmeister CM, Huang R, Osso LA, Thornton MA, Conant L, Chavez AR, et al. Motor learning drives dynamic patterns of intermittent myelination on learning-activated axons. Nat Neurosci. 2022;25:1300–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, Richardson WD. Motor skill learning requires active central myelination. Science. 2014;346:318–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Doron A, Rubin A, Benmelech-Chovav A, Benaim N, Carmi T, Refaeli R, et al. Hippocampal astrocytes encode reward location. Nature. 2022;609:772–8.

    CAS  PubMed  Google Scholar 

  150. Kol A, Adamsky A, Groysman M, Kreisel T, London M, Goshen I. Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat Neurosci. 2020;23:1229–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T, et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell. 2018;174:59–71.e14.

    CAS  PubMed  Google Scholar 

  152. Cho W-H, Noh K, Lee BH, Barcelon E, Jun SB, Park HY, et al. Hippocampal astrocytes modulate anxiety-like behavior. Nat Commun. 2022;13:6536.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Cao P, Chen C, Liu A, Shan Q, Zhu X, Jia C, et al. Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines. Neuron. 2021;109:2573–2589.e9.

    CAS  PubMed  Google Scholar 

  154. Allen M, Huang BS, Notaras MJ, Lodhi A, Barrio-Alonso E, Lituma PJ, et al. Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling. Mol Psychiatry. 2022;27:2470–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Hou G, Lai W, Jiang W, Liu X, Qian L, Zhang Y, et al. Myelin deficits in patients with recurrent major depressive disorder: An inhomogeneous magnetization transfer study. Neurosci Lett. 2021;750:135768.

    CAS  PubMed  Google Scholar 

  156. Jiang L, Cheng Y, Jiang H, Xu J, Lu J, Shen Z, et al. Association between abnormal serum myelin-specific protein levels and white matter integrity in first-episode and drug-naïve patients with major depressive disorder. J Affect Disord. 2018;232:61–68.

    CAS  PubMed  Google Scholar 

  157. Boda E. Myelin and oligodendrocyte lineage cell dysfunctions: New players in the etiology and treatment of depression and stress-related disorders. Eur J Neurosci. 2021;53:281–97.

    CAS  PubMed  Google Scholar 

  158. Thornton MA, Futia GL, Stockton ME, Budoff SA, Ramirez AN, Ozbay B, et al. Long-term in vivo three-photon imaging reveals region-specific differences in healthy and regenerative oligodendrogenesis. bioRxiv 2023.10.29.564636 (2023). https://doi.org/10.1101/2023.10.29.564636.

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Funding

MAK: National Institute of Mental Health R01 MH108623, R01 MH111754, R01 MH117961, R01 MH125515, National Institute on Deafness and Other Communication Disorders R01 DC019813, One Mind Rising Star Award, Human Frontier Science Program RGY0072/2019, Esther A. and Joseph Klingenstein Fund, Pew Charitable Trusts, McKnight Memory and Cognitive Disorders Award. MMG: National Institute of Mental Health F31 MH130127, National Institute of Neurological Disorders and Stroke DSPAN F99/K00 NS130927.

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Authors and Affiliations

  1. Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA, USA

    Mark M. Gergues, Lahin K. Lalani & Mazen A. Kheirbek

  2. Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA

    Mark M. Gergues, Lahin K. Lalani & Mazen A. Kheirbek

  3. Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    Mark M. Gergues, Lahin K. Lalani & Mazen A. Kheirbek

  4. Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, USA

    Mazen A. Kheirbek

  5. Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA, USA

    Mazen A. Kheirbek

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Gergues, M.M., Lalani, L.K. & Kheirbek, M.A. Identifying dysfunctional cell types and circuits in animal models for psychiatric disorders with calcium imaging. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01942-y

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