Synaptic mechanisms for differential severity of social preference deficits in male and female mice induced by diminished activity-dependent BDNF
TL;DR
Synaptic mechanisms underlying the differential severity of social preference deficit in male and female BDNF+/Met mice are revealed, which provides a potential neural basis for sex differences in male and female ASD patients with and without the BDNF Val66Met SNP.
Abstract
Males are more commonly diagnosed with autism spectrum disorder (ASD) than females with a ratio of about 4–1. However, the neural mechanisms underlying the sex differences in ASD are unknown. Social deficits are the core symptoms of patients with ASD. Previous studies showed that diminished activity-dependent brain-derived neurotrophic factor (BDNF) signaling induced differential severity of autism-like social preference deficits in male and female mice by using a mouse model with genetic knock-in of human BDNF methionine (Met) allele, which significantly decreased activity-dependent BDNF release without affecting basal BDNF secretion. Here, we investigated the synaptic mechanisms for diminished activity-dependent BDNF-induced differential severity of social preference deficits in males and females. The prefrontal cortex (PFC) is a critical brain region for social behaviors. Whole-cell patch-clamp brain slice recordings showed that diminished activity-dependent BDNF signaling differentially increased the frequency of spontaneous action potentials (sAPs) of pyramidal neurons in the PFC of male and female BDNF+/Met mice. The frequency of sAPs in male BDNF+/Met mice was higher than in female BDNF+/Met mice. Diminished activity-dependent BDNF signaling differentially enhanced excitatory synaptic transmission and dampened inhibitory synaptic transmission of pyramidal neurons at pre- and post- synapses in males and females, which were mediated by dysregulated transcriptional levels of key synaptic genes. Chemogenetic inhibition of pyramidal neurons in the PFC of BDNF+/Met mice was sufficient to ameliorate autism-like social preference deficits in males and females. This study reveals synaptic mechanisms underlying the differential severity of social preference deficit in male and female BDNF+/Met mice, which provides a potential neural basis for sex differences in male and female ASD patients with and without the BDNF Val66Met SNP.