title: 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.
abstract: 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, we employed 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.
authors.affiliation: Howard Florey Institute, Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Manning
authors.forename: Mark I
authors.initials: MI
authors.lastname: Ransome
authors.forename: Emma L
authors.initials: EL
authors.lastname: Burrows
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
mesh_terms: D053687:Adult Stem Cells / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000473:pathology; D055495:Neurogenesis; D009474:Neurons / Q000473:pathology*; D054799:Phospholipase C beta / Q000172:deficiency* / Q000235:genetics; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
chemical_list: D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse