Synaptic mechanisms for differential severity of social preference deficits in male and female mice induced by diminished activity-dependent BDNF.

Authors

Kaijie Ma, Maria Webb, Samuel S Newton, Francis S Lee, Luye Qin

Published in

Frontiers in neuroscience. Volume 20. Pages 1864866. Epub Jul 27, 2026.

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.

PMID:
42577364
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.