Cell-Specific Disruptions in the Basolateral Amygdala-Accumbens Pathway of Fragile X mouse

Abstract

Fragile X syndrome (FXS), a neurodevelopmental disorder caused by the inactivation of the FMR1 gene, is one of the most common causes of autism spectrum disorder (ASD). People with FXS and ASD often have difficulty regulating their emotions and behaving in a socially appropriate way. The specific neuronal circuits and synaptic dysfunctions involved in social deficits in FXS are not yet fully understood. The basolateral amygdala to accumbens pathway is central to normal social behavior, and we investigated the functionality of this pathway in a novel mouse model of FXS (Fmr1/y::Drd1a-tdTomato). We used optogenetics to distinguish synapses between BLA neurons and spiny projection neurons in the NAcC. We found that the BLA-NAcC connection in FXS mice displayed heightened synaptic strength along with specific alterations in synaptic plasticity. In FXS, enhanced AMPA and NMDA postsynaptic currents elevated BLA-D2 SPN synaptic strength, while BLA-D1 SPNs increased firing probability occurred without altered transmission. This results in an overall increase in postsynaptic integration in both D1 and D2 SPN BLA-NAcC pathways compared to WT littermates. Further, the absence of FMRP leads to a specific deficit in long-term depression for BLA-D1 SPNs connections. The neurobiological changes identified in this study may underlie the susceptibility to stressors, socio-communicative difficulties, and altered reward-related processes that are characteristic of FXS pathology.