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

Haan, Niels, Westacott, Laura J., Carter, Jenny, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Gray, William P. ORCID: https://orcid.org/0000-0001-7595-8887, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009 and Wilkinson, Lawrence S. ORCID: https://orcid.org/0000-0002-9337-6124 2021. Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms. Translational Psychiatry 11 (1) , 313. 10.1038/s41398-021-01415-6

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Psychology Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Springer Nature
ISSN:	2158-3188
Funders:	Wellcome Trust
Date of First Compliant Deposit:	7 June 2021
Date of Acceptance:	4 May 2021
Last Modified:	14 Sep 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/141757

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