Knockout of p75NTR in Cerebellar Purkinje Cells Results in an Autism-like Murine Phenotype (P4.337)

OBJECTIVE: We sought to test the hypothesis that knockout of the p75 neurotrophin receptor (p75NTR) in murine cerebellar Purkinje cells results in an autism-like behavioral and neuroanatomic phenotype. BACKGROUND: p75NTR is normally expressed in cerebellar Purkinje cells throughout the lifespan. Children with autism spectrum behavior exhibit apparent cerebellar Purkinje cell loss. Cerebellar transcriptome changes seen in the murine prenatal valproate exposure model of autism include all of the proteins known to constitute the p75NTR interactome. p75NTR is a modulator of cytoplasmic and mitochondrial redox potential, and others have suggested that aberrant response to oxidant stress plays a major role in the pathogenesis of autism. Twenty of the 39 genes of the known p75NTR interactome are highly correlated with SFARI genes implicated in human autism; and 18 are themselves implicated in neurobehavioral and/or neurodegenerative disorders. DESIGN/METHODS: We have created Purkinje cell-selective p75NTR knockout mice that are the progeny of hemizygous cre-Purkinje cell protein 2 (PCP2) C57Bl mice and p75NTR floxed C57Bl mice. (We refer hereafter to mice bearing both cre and loxP as “cre-loxP mice”.) RESULTS: Cre-loxP mice exhibit complete knockout of p75NTR in approximately 50% of the cerebellar Purkinje cells. Relative to cre-only mice and wild type C57Bl mice, this results in a behavioral phenotype characterized by less allogrooming of (p<0.05) and socialization or fighting with (each p<0.05) other mice; less (1.2-fold) non-ambulatory exploration of their environment than wild-type (p<0.01) or cre only (p<0.01) mice; and almost 2-fold more stereotyped jumping behavior than wild type (p<0.05; Fisher’s PLSD) or cre (p<0.02) mice of the same strain. Wild type mice have a larger number of neurites (2-fold) with more branches off of primary neurites (4-fold) than cre-loxP mice (p<0.001 in each case). CONCLUSIONS: Aberrant developmental regulation of expression of p75NTR in cerebellar Purkinje cells may contribute to the pathogenesis of autism. STUDY SUPPORTED BY: Strong Children9s Research Center and the William H. Eilinger Endowment of Golisano Children9s Hospital at URMC. Disclosure: Dr. Schor has nothing to disclose. Dr. Cory-Slechta has nothing to disclose. Dr. Lotta has nothing to disclose. Dr. Conrad has nothing to disclose.