Amelioration of biased neuronal differentiation in humanized mouse model of valproic acid-induced autism by precisely targeted transcranial magnetic stimulation

Abstract

Autism spectrum disorder (ASD) is a group of developmental diseases, which still lacks effective treatments. Pregnant exposure of Valproic acid (VPA) is an important environmental risk factor for ASD, but it's long-term effects on the development of human neural cells, particularly in vivo, and the corresponding treatment have yet been fully investigated. In the present study, we first made a humanized ASD mouse model by transplanting VPA-pretreated human neural progenitor cells (hNPCs) into the cortex of immune-deficient mice. In comparison with wild type and control chimeric mice, ASD chimeric mice (^VPAhNPC mice) exhibit core syndromes of ASD, namely dramatic reduction of sociability, social interaction and social communication, and remarkable increase of stereotype repetitive behaviors and anxiety-like behaviors. At cellular level, VPA-pretreatment biased the differentiation of human excitatory neurons and their axonal projections in host brain. Chemogenetic suppression of human neuronal activity restored most behavior abnormalities of ^VPAhNPC mice. Further, specific modulation of human neurons by a newly developed transcranial magnetic stimulation (TMS) device which could precisely target hPNCs effectively recued the core syndromes of ASD-like behaviors, restored the excitatory-inhibitory neuronal differentiation and axonal projection, and reversed the expression of over half of the VPA-affected genes. These data demonstrated that ^VPAhNPC mice could be used as a humanized model of ASD and that precisely targeted TMS could ameliorate the VPA-biased human neuronal differentiation in vivo.