PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

• DOI: 10.1016/j.celrep.2017.12.044
• Publication Date: 2018-01-09T16:43:00Z
• Authors: Xiao-Feng Zhao; Rafi Kohen; Rachel Parent; Yuntao Duan; Grace L. Fisher; Matthew J. Korn; Lingchao Ji; Guoqiang Wan; Jing Jin; Andreas W. Püschel; David F. Dolan; Jack M. Parent; Gabriel Corfas; Geoffrey G. Murphy; Roman J. Giger
• Keywords: Granule cell; DISC1; Small GTPase

Dentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well their proliferation and migration into primordial DG. We identify Plexin family members Plxna2 Plxna4 important regulators DG development. Distribution immature GCs is regulated by Sema5A signaling through PlxnA2 a functional GTPase-activating protein (GAP) domain Rap1 small GTPases. In adult Plxna2−/− but not Plxna2-GAP-deficient mice, dentate GC layer severely malformed, neurogenesis compromised, mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with mice revealed deficits associative learning, sociability, sensorimotor gating—traits commonly observed neuropsychiatric disorder. Remarkably, while morphological defects are minimal brains, fear memory gating persist. Since allelic variants human PLXNA2 RAP1 associate schizophrenia, our biochemical pathway for brain mental health.