Maternal pesticide exposure disrupts local inhibitory circuits in the reward pathway.

Maternal exposure to the pyrethroid pesticide deltamethrin (DM), even below the No Observed Adverse Effect Level (NOAEL), has been increasingly associated with models of neurodevelopmental disorders (NDDs) such as attention-deficit hyperactivity disorder (ADHD) and autism-spectrum disorders (ASD). While recent studies have documented the impact of maternal DM exposure on offspring hippocampal circuits, its effects on the nucleus accumbens (NAc)-a key region implicated in NDDs-remain poorly understood. The NAc is composed of over 80% medium spiny neurons (MSNs), which serve as its sole output and rely on specialized local inhibitory interneurons to regulate firing patterns and synaptic integration. Here, we report subtype-specific dysfunction in parvalbumin-positive (PV+) inhibitory interneurons in the NAc of offspring following maternal DM exposure in mice. Whole-cell patch-clamp recordings from genetically labeled PV+ interneurons revealed that high input-resistance (IR) PV interneurons exhibited unique vulnerability. DM exposure significantly reduced maximum firing frequency and lowered action potential threshold, while low IR PV interneurons remained unaffected. Additionally, the probability of more frequent excitatory synaptic inputs onto high IR PV interneurons were significantly reduced. Mapping our data onto publicly available patch-seq data from a Mini-Atlas revealed that high IR PV interneurons express high levels of Shisa8, an accessory protein regulating AMPA receptor kinetics, and low levels of Grin2A, an NMDA receptor component, suggesting that specific local synaptic circuit disruption in DM-sensitive neurons. Thus, maternal DM exposure selectively impairs a subtype of inhibitory interneurons with unique physiological properties, potentially disrupting synaptic integration in the reward circuit and contributing to NDD-like phenotypes.