Increased adult hippocampal neurogenesis and abnormal migration of adult-born granule neurons is associated with hippocampal-specific cognitive deficits in phospholipase C-β1 knockout mice

Schizophrenia is a devastating psychiatric illness with a complex pathophysiology. We have recently documented schizophrenia-like endophenotypes in phospholipase C-β1 knockout (PLC-β1 ^-/-) mice, including deficits in prepulse inhibition, hyperlocomotion, and cognitive impairments. PLC-β1 signals via multiple G-protein coupled receptor pathways implicated in neural cellular plasticity; however, adult neurogenesis has yet to be explored in this knockout model. In this study, weemployed PLC-β1 ^-/- mice to elucidate possible correlates between aberrant adult hippocampal neurogenesis (AHN) and schizophrenia-like behaviors. Using stereology and bromodeoxyuridine (BrdU) immunohistochemistry we demonstrated a significant increase in the density of adult-generated cells in the granule cell layer (GCL) of adult PLC-β1 ^-/- mice compared with wild-type littermates. Cellular phenotype analysis using confocal microscopy revealed these cells to be mature granule neurons expressing NeuN and calbindin. Increased neuronal survival occurred concomitant with reduced caspase-3(+) cells in the GCL of PLC-β1 ^-/- mice. Stereological analysis of Ki67(+) cells in the subgranular zone suggested that neural precursor proliferation is unchanged in PLC-β1 ^-/- mice. We further showed aberrant migration of mature granule neurons within the GCL of adult PLC-β1 ^-/- mice with excessive adult-generated mature neurons residing in the middle and outer GCL. PLC-β1 ^-/- mice exhibited specific behavioral deficits in location recognition, a measure of hippocampal-dependent memory, but not novel object recognition. Overall, we have shown that PLC-β1 ^-/- mice have a threefold increase in net AHN, and have provided further evidence to suggest a specific deficit in hippocampal-dependent cognition. We propose that abnormal cellular plasticity in these mice may contribute to their schizophrenia-like behavioral endophenotypes.