RT Journal Article SR Electronic T1 Haploinsufficiency of the schizophrenia risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through a novel microglia dependent mechanism JF bioRxiv FD Cold Spring Harbor Laboratory SP 417832 DO 10.1101/417832 A1 Niels Haan A1 Jenny Carter A1 Laura J Westacott A1 Michael J Owen A1 William P Gray A1 Jeremy Hall A1 Lawrence S Wilkinson YR 2018 UL http://biorxiv.org/content/early/2018/09/14/417832.abstract AB Genetic and epidemiological evidence implicate the immune system in the pathogenesis of schizophrenia but mechanistic insights are lacking. Here we show that haploinsufficiency of Cyfip1 a candidate risk gene for schizophrenia in the pathogenic 15q11.2(BP1-BP2) deletion impacts on microglia the resident immune cells of the central nervous system to cause abnormal neurogenesis in the postnatal hippocampus. We use mouse models to first demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult born hippocampal neurons without altering proliferation. We next show that the increased numbers of new born neurons are due to reduced apoptosis of immature neurons. We then demonstrate that apoptosis of immature neurons is controlled by secreted factors from microglia. Finally we show that haploinsufficiency of Cyfip1 leads to a cell autonomous failure of microglia induced neuronal apoptosis, resulting in sparing of immature neurons that would normally have been culled at this developmental check-point, with implications for maladaptive function. Our findings provide a novel mechanism linking a psychiatric risk gene with microglial dysfunction in the hippocampus, a brain area with strong evidence for involvement in psychopathology.