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Cited by 29Neurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration MechanismsSchizophrenia research and treatment

Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

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Haan, Niels, Westacott, Laura J., Carter, Jenny, Owen, Michael J., Gray, William P., Hall, Jeremy, Wilkinson, Lawrence S.·2021·Translational Psychiatry
DOI 10.1038/s41398-021-01415-6PMC PMC8144403
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Abstract

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

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  • Mice with Cyfip1 haploinsufficiency have abnormal postnatal hippocampal neurogenesis.

    “Mice with Cyfip1 haploinsufficiency have been found to have a reduced number of synapses in the hippocampus [2], and have abnormal postnatal hippocampal neurogenesis [80].”

    From Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility (2024) · cites this paper as [80]

  • CYFIP1 also regulates adult hippocampal neurogenesis via cell-autonomous and non-cell-autonomous mechanisms.

    “CYFIP1 also regulates adult hippocampal neurogenesis via cell-autonomous and non-cell-autonomous mechanisms76.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [76]

  • Haploinsufficiency of mouse Cyfip1 results in increased numbers of adult-born hippocampal neurons due to reduced apoptosis without altering proliferation via a failure of microglia to induce apoptosis through the secretion of appropriate factors.

    “Haploinsufficiency of mouse Cyfip1 results in increased numbers of adult-born hippocampal neurons due to reduced apoptosis without altering proliferation via a failure of microglia to induce apoptosis through the secretion of appropriate factors76.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [76]

  • Haploinsufficiency of Cyfip1 causes abnormal migration of adult-born neurons due to altered ARP2/3-mediated actin dynamics.

    “In addition, haploinsufficiency of Cyfip1 causes abnormal migration of adult-born neurons due to altered ARP2/3-mediated actin dynamics76.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [76]

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  1. [1]Pardiñas, A. F. et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat. Genet. 10.1038/s41588-018-0059-2 (2018). PMC5918692 29483656 · DOI · Paper page
  2. [3]Hall J Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity Biol. Psychiatry 2015 77 52 58 10.1016/j.biopsych.2014.07.011 25152434 · DOI · Paper page
  3. [4]Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways Nat. Neurosci. 2015 18 199 209 10.1038/nn.3922 25599223 PMC4378867 · DOI · Paper page
  4. [6]Stefansson H Large recurrent microdeletions associated with schizophrenia Nature 2008 455 232 236 10.1038/nature07229 18668039 PMC2687075 · DOI · Paper page
  5. [7]Kirov G Support for the involvement of large copy number variants in the pathogenesis of schizophrenia Hum. Mol. Genet 2009 18 1497 1503 10.1093/hmg/ddp043 19181681 PMC2664144 · DOI · Paper page
  6. [8]Zhao Q Rare CNVs and tag SNPs at 15q11.2 are associated with schizophrenia in the Han Chinese population Schizophr. Bull. 2013 39 712 719 10.1093/schbul/sbr197 22317777 PMC3627771 · DOI · Paper page
  7. [10]Oguro-Ando A Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR Mol. Psychiatry 2015 20 1069 1078 10.1038/mp.2014.124 25311365 PMC4409498 · DOI · Paper page
  8. [11]Hsiao K Cyfip1 regulates presynaptic activity during development J. Neurosci. 2016 36 1564 1576 10.1523/JNEUROSCI.0511-15.2016 26843638 PMC4737770 · DOI · Paper page
  9. [13]Chen Z Structure and control of the actin regulatory WAVE complex Nature 2010 468 533 538 10.1038/nature09623 21107423 PMC3085272 · DOI · Paper page
  10. [14]Spalding KL Dynamics of hippocampal neurogenesis in adult humans Cell 2013 153 1219 1227 10.1016/j.cell.2013.05.002 23746839 PMC4394608 · DOI · Paper page
  11. [15]Kempermann G Song H Gage FH Neurogenesis in the adult hippocampus Cold Spring Harb. Perspect. Biol. 2015 7 a018812 10.1101/cshperspect.a018812 26330519 PMC4563705 · DOI · Paper page
  12. [16]Clelland CD A functional role for adult hippocampal neurogenesis in spatial pattern separation Science 2009 325 210 213 10.1126/science.1173215 19590004 PMC2997634 · DOI · Paper page
  13. [17]Sahay A Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation Nature 2011 472 466 470 10.1038/nature09817 21460835 PMC3084370 · DOI · Paper page
  14. [19]Dupret D Spatial relational memory requires hippocampal adult neurogenesis PLoS ONE 2008 3 e1959 10.1371/journal.pone.0001959 18509506 PMC2396793 · DOI
  15. [20]Akers KG Hippocampal neurogenesis regulates forgetting during adulthood and infancy Science 2014 344 598 602 10.1126/science.1248903 24812394 · DOI · Paper page
  16. [21]Seo D-O Adult hippocampal neurogenesis modulates fear learning through associative and nonassociative mechanisms J. Neurosci. 2015 35 11330 11345 10.1523/JNEUROSCI.0483-15.2015 26269640 PMC4532761 · DOI
  17. [22]Deng W Saxe MD Gallina IS Gage FH Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain J. Neurosci. 2009 29 13532 13542 10.1523/JNEUROSCI.3362-09.2009 19864566 PMC2787190 · DOI · Paper page
  18. [23]Martinelli C Shergill SS Clarifying the role of pattern separation in schizophrenia: the role of recognition and visual discrimination deficits Schizophr. Res. 2015 166 328 333 10.1016/j.schres.2015.06.004 26117156 · DOI
  19. [24]Das T Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction Schizophr. Res. 2014 159 193 197 10.1016/j.schres.2014.05.006 25176349 PMC4177293 · DOI
  20. [25]Salgado-Pineda P Examining hippocampal function in schizophrenia using a virtual reality spatial navigation task Schizophr. Res 2016 172 86 93 10.1016/j.schres.2016.02.033 26924620 · DOI
  21. [27]Newton SS Duman RS Neurogenic actions of atypical antipsychotic drugs and therapeutic implications CNS Drugs 2007 21 715 725 10.2165/00023210-200721090-00002 17696572 · DOI
  22. [28]Ye F DISC1 regulates neurogenesis via modulating kinetochore attachment of Ndel1/Nde1 during mitosis Neuron 2017 96 1041 1054.e5 10.1016/j.neuron.2017.10.010 29103808 PMC5731645 · DOI
  23. [29]Chen Q SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory Eur. J. Neurosci. 2012 36 2597 2608 10.1111/j.1460-9568.2012.08180.x 22697179 PMC3466408 · DOI
  24. [30]Temme, S. J., Bell, R. Z., Fisher, G. L. & Murphy, G. G. Deletion of the mouse homolog of CACNA1C disrupts discrete forms of hippocampal-dependent memory and neurogenesis within the dentate gyrus. eNeuro310.1523/ENEURO.0118-16.2016 (2016). PMC5124786 27957527 · DOI
  25. [31]Moon, A. L. et al. CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis. Schizophr. Bull. 10.1093/schbul/sby096 (2018). PMC6101623 29982775 · DOI
  26. [32]Ouchi Y Reduced adult hippocampal neurogenesis and working memory deficits in the Dgcr8-deficient mouse model of 22q11.2 deletion-associated schizophrenia can be rescued by IGF2 J. Neurosci. 2013 33 9408 9419 10.1523/JNEUROSCI.2700-12.2013 23719809 PMC6618567 · DOI · Paper page
  27. [33]Smrt RD MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1 Stem Cells 2010 28 1060 1070 10.1002/stem.431 20506192 PMC3140955 · DOI · Paper page
  28. [34]Barbeau D Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains Proc. Natl Acad. Sci. U.S.A. 1995 92 2785 2789 10.1073/pnas.92.7.2785 7708724 PMC42303 · DOI
  29. [36]Allen KM Fung SJ Shannon Weickert C Cell proliferation is reduced in the hippocampus in schizophrenia Aust. N. Z. J. Psychiatry 2016 50 473 480 10.1177/0004867415589793 26113745 PMC4843086 · DOI
  30. [38]Knuesel I Maternal immune activation and abnormal brain development across CNS disorders Nat. Rev. Neurol. 2014 10 643 660 10.1038/nrneurol.2014.187 25311587 · DOI · Paper page
  31. [41]Bloomfield PS Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [11 C]PBR28 PET brain imaging study Am. J. Psychiatry 2016 173 44 52 10.1176/appi.ajp.2015.14101358 26472628 PMC4821370 · DOI
  32. [42]Holmes SE In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study Mol. Psychiatry 2016 21 1672 1679 10.1038/mp.2016.180 27698434 · DOI
  33. [43]Notter T Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia Mol. Psychiatry 2018 23 323 334 10.1038/mp.2016.248 28093569 · DOI
  34. [44]Notter T Coughlin JM Sawa A Meyer U Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry Mol. Psychiatry 2018 23 36 47 10.1038/mp.2017.232 29203847 · DOI
  35. [45]Paolicelli RC Synaptic pruning by microglia is necessary for normal brain development Science 2011 333 1456 1458 10.1126/science.1202529 21778362 · DOI · Paper page
  36. [47]Kim H-J Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects Mol. Psychiatry 2017 22 1576 1584 10.1038/mp.2016.103 27400854 PMC5658669 · DOI · Paper page
  37. [48]Li Y Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo Dev. Cell 2012 23 1189 1202 10.1016/j.devcel.2012.10.027 23201120 · DOI
  38. [49]Cunningham CL Martinez-Cerdeno V Noctor SC Microglia regulate the number of neural precursor cells in the developing cerebral cortex J. Neurosci. 2013 33 4216 4233 10.1523/JNEUROSCI.3441-12.2013 23467340 PMC3711552 · DOI · Paper page
  39. [50]Brown GC Neher JJ Microglial phagocytosis of live neurons Nat. Rev. Neurosci. 2014 15 209 216 10.1038/nrn3710 24646669 · DOI · Paper page
  40. [51]Haan N Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus J. Neurosci. 2013 33 6170 6180 10.1523/JNEUROSCI.2437-12.2013 23554498 PMC3736310 · DOI
  41. [52]Meijering, E., Dzyubachyk, O. & Smal, I. Methods for cell and particle tracking. In: Methods in Enzymology. Academic Press Inc., 2012, pp 183–200. 22264535
  42. [54]Kohman RA Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice Behav. Brain Res. 2013 242 17 24 10.1016/j.bbr.2012.12.032 23274840 PMC3725815 · DOI
  43. [55]Mattei D Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia Brain Behav. Immun. 2014 38 175 184 10.1016/j.bbi.2014.01.019 24509090 · DOI
  44. [57]Chemin K Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity J. Immunol. 2012 189 2159 2168 10.4049/jimmunol.1200156 22821962 · DOI
  45. [58]Drew, J. et al. Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1. bioRxiv10.1101/2020.05.31.124941 (2020). PMC12993954 41818151
  46. [59]Schaks, M. et al. Distinct interaction sites of Rac GTPase with WAVE regulatory complex have non-redundant functions in vivo. Curr. Biol. 10.1016/j.cub.2018.10.002 (2018). PMC6264382 30393033 · DOI · Paper page
  47. [60]Chen, B. et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife10.7554/eLife.29795. (2017). PMC5614565 28949297
  48. [61]Vivar C Monosynaptic inputs to new neurons in the dentate gyrus Nat. Commun. 2012 3 1107 10.1038/ncomms2101 23033083 PMC4603575 · DOI
  49. [62]Tashiro, A. et al. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature44210.1038/nature05028 (2006). 16906136 · DOI
  50. [63]Bachmann SO Behavioral training rescues motor deficits in Cyfip1 haploinsufficiency mouse model of autism spectrum disorders Transl. Psychiatry 2019 9 29 10.1038/s41398-018-0338-9 30664619 PMC6341103 · DOI
  51. [64]Domínguez-Iturza N The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour Nat. Commun. 2019 10 3454 10.1038/s41467-019-11203-y 31371726 PMC6672001 · DOI · Paper page
  52. [65]Silva AI Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility Nat. Commun. 2019 10 3455 10.1038/s41467-019-11119-7 31371763 PMC6671959 · DOI · Paper page
  53. [66]Chaste P Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2 Autism Res. 2014 7 355 362 10.1002/aur.1378 24821083 PMC6003409 · DOI · Paper page
  54. [67]Abdelmoity AT 15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features J. Dev. Behav. Pediatr. 2012 33 570 576 10.1097/DBP.0b013e31826052ae 22922608 · DOI · Paper page
  55. [69]Tay TL Microglia gone rogue: impacts on psychiatric disorders across the lifespan Front. Mol. Neurosci. 2018 10 421 10.3389/fnmol.2017.00421 29354029 PMC5758507 · DOI
  56. [70]Jones KA Thomsen C The role of the innate immune system in psychiatric disorders Mol. Cell. Neurosci. 2013 53 52 62 10.1016/j.mcn.2012.10.002 23064447 · DOI · Paper page

Cited by

Sorted by citations

Authors
Haan, N., Westacott, L. J., Carter, J., Owen, M. J., Gray, W. P., Hall, J., & Wilkinson, L. S.
Affiliations
Cardiff University (GB)
Corresponding author
Haan, Niels
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-05-24
Volume
11
Issue
1
Pages
313-313
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-021-01415-6
PMC
PMC8144403
OpenAlex
W3164422365
Cited by
29
References
14
Citations by year
2026: 3 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Wellcome Trust (100202/Z/12/Z)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
CYFIP1, haploinsufficiency, schizophrenia, autism spectrum disorder, adult neurogenesis, microglia, apoptosis, Arp2/3 complex, actin dynamics, neuronal migration, risk genes, psychopathology
MeSH terms
Actins, Adult, Autistic Disorder, Hippocampus, Humans, Infant, Newborn, Schizophrenia, Microglia, Adaptor Proteins, Signal Transducing, Neurogenesis, Haploinsufficiency

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