Agbl4 deficiency links neuropsychiatric risk to prefrontal inhibitory dysfunction and its pharmacological rescue

초록

Mutations in AGBL4 have been associated with neurodevelopmental and psychiatric disorders such as autism spectrum disorder (ASD) and depression, but its mechanistic role in brain function remains elusive. Here, we demonstrate that Agbl4 knockout (KO) mice exhibit selective impairments in social behavior and increased depressive-like behavior, accompanied by elevated excitation/inhibition (E/I) ratio in the medial prefrontal cortex (mPFC). These synaptic alterations were characterized by reduced GABAergic transmission and hyperexcitability of pyramidal neurons, pointing to impaired inhibitory network function in the mPFC. Notably, acute low-dose clonazepam (CLZ) treatment, a positive allosteric modulator of GABAA receptors, restored both inhibitory synaptic activity and behavioral deficits. This pharmacological rescue underscores the causal role of inhibitory dysfunction in the AGBL4 phenotype. Together, our findings highlight AGBL4 as a regulator of prefrontal inhibitory circuits and suggest that enhancing GABAergic signaling represents a tractable therapeutic strategy for AGBL4-associated neurodevelopmental disorders.