Abstract
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.