Work

Hyperactive lateral hypothalamic GABAergic neurons drive abnormal aggression in neuroligin-3 R451C knock-in mice

Year: 2026

Type: article

Abstract: Aggressive behaviors represent a common and clinically challenging comorbidity in individuals with autism spectrum disorder (ASD), yet the underlying neural mechanisms remain poorly understood. This study aimed to investigate the circuit-level pathology driving elevated aggression in Neuroligin-3 R451C knock-in mice (NL3 R451C or KI mice). Aggressive behaviors in adult male mice were assessed using the resident-intruder and self-initiated aggression tests. Following the R-I test, c-Fos brain mapping was performed. Fiber photometry recording was used to capture neuronal activity in selected brain regions during attack bouts. Chemogenetic inhibition was applied to establish the causal role of specific neuronal subtypes or circuits in elevated aggression. Additive NL3 expression was used to examine the genetic contribution of distinct neuronal subpopulations to maladaptive aggression. NL3 R451C mice exhibited heightened aggression and aggression-seeking behavior, accompanied by increased c-Fos expression in multiple brain regions, including the lateral hypothalamus (LH), prelimbic cortex (PrL), and ventral tegmental area (VTA). During attacks, KI mice showed enhanced calcium transients in LH GABAergic neurons and in PrL →LH glutamatergic neurons, but not in LH glutamatergic neurons. Critically, chemogenetic suppression of LH GABAergic neurons, or of LH neurons projecting to the VTA or periaqueductal gray (PAG), attenuated excessive aggression in KI mice, whereas inhibition of PrL →LH neurons had no effect. Moreover, additive NL3 expression specifically in LH GABAergic neurons, but not in PrL neurons, was sufficient to ameliorate the aggressive phenotype. First, the synaptic mechanisms underlying LH GABAergic dysregulation remain to be defined by direct electrophysiological characterization. Second, LH GABAergic neurons are heterogeneous, and our approach did not identify which specific subtype mediates excessive aggression. Third, our study used a male‑only design, reflecting the X‑linked clinical presentation of the NL3 R451C mutation. Future studies in female mutants could provide insights into sexual dimorphism and the underlying mechanisms. Fourth, NL3 rescue was achieved via viral‑mediated adult additive expression rather than developmental precisely genetic correcting. We conclude that hyperactive LH GABAergic neurons, caused by NL3 loss, is a core pathological mechanism underlying abnormal aggression in NL3 R451C mouse model of ASD.

Source: Molecular Autism

DOI: 10.1186/s13229-026-00741-0