Cell- and Pathway-Specific Disruptions in the Accumbens of Fragile X Mouse

Abstract

Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism spectrum disorder (ASD), associated with social deficits. The mesocorticolimbic system, which includes the prefrontal cortex (PFC), basolateral amygdala (BLA), and nucleus accumbens core (NAcC), is essential for regulating socio-emotional behaviors. We employed optogenetics to compare the functional properties of the BLA→NAcC, PFC→NAcC, and reciprocal PFC↔BLA pathways inFmr1−/y::Drd1a-tdTomatomale mice. In FXS mice, the PFC↔BLA reciprocal pathway was unaffected, while significant synaptic modifications occurred in the BLA/PFC→NAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications in D2 SPNs. In FXS mice, the BLA/PFC→NAcC-D2 SPNs pathways demonstrated heightened synaptic strength. Focusing on the BLA→NAcC pathway, linked to autistic symptoms, we found increased AMPAR and NMDAR currents, and elevated spine density in D2 SPNs. Conversely, the amplified firing probability of BLA→NAcC-D1 SPNs was not accompanied by increased synaptic strength, AMPAR and NMDAR currents, or spine density. These pathway-specific alterations resulted in an overall enhancement of excitatory-to-spike coupling, a physiologically relevant index of how efficiently excitatory inputs drive neuronal firing, in both BLA→NAcC-D1 and BLA→NAcC-D2 pathways. Finally, the absence of FMRP led to impaired long-term depression specifically in BLA→D1 SPNs. These distinct alterations in synaptic transmission and plasticity within circuits targeting the NAcC highlight the potential role of postsynaptic mechanisms in selected SPNs in the observed circuit-level changes. This research underscores the heightened vulnerability of the NAcC in the context of FMRP deficiency, emphasizing its pivotal role in the pathophysiology of FXS.Significance StatementFragile X Syndrome is a neurodevelopmental disorder characterized by significant emotional dysregulation and social challenges. The mesocorticolimbic system is a key socioemotional regulator. Nevertheless, its functioning in this condition is still poorly understood. Our study investigates connections between the basolateral amygdala (BLA), prefrontal cortex (PFC), and nucleus accumbens core (NAcC). We observed that while the PFC↔BLA reciprocal connections remained unaffected, their projections onto the NAcC showed target cell-specific changes. Specifically, D2 SPNs exhibited increased synaptic transmission and spine density, whereas D1 SPNs showed heightened firing probability and impaired long-term depression, alongside enhanced neuronal firing efficiency in both SPN types. These findings emphasize the NAcC's crucial role as a neurobiological substrate in the pathophysiology of Fragile X Syndrome.