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

Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism spectrum disorder. The mesocorticolimbic system, which includes the prefrontal cortex (PFC), basolateral amygdala (BLA), and nucleus accumbens core (NAcC), is essential for regulating socioemotional behaviors. We employed optogenetics to compare the functional properties of the BLA-+NAcC,-+ NAcC, PFC-+NAcC,-+ NAcC, and reciprocal PFCHBLA H BLA pathways in Fmr1-/y::Drd1a-tdTomato - /y::Drd1a-tdTomato male mice. In FXS mice, the PFCHBLA H BLA reciprocal pathway was unaffected, while significant fi cant synaptic modifications fi cations occurred in the BLA/PFC-+NAcC-+ NAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications fi cations in D2 SPNs. In FXS mice, the BLA/PFC-+NAcC-D2-+ NAcC-D2 SPN pathways demonstrated heightened synaptic strength. Focusing on the BLA-+NAcC-+ NAcC pathway, linked to autistic symptoms, we found increased AMPAR and NMDAR currents and elevated spine density in D2 SPNs. Conversely, the amplified fi ed fi ring probability of BLA-+NAcC--+ NAcC- D1 SPNs was not accompanied by increased synaptic strength, AMPAR and NMDAR currents, or spine density. These pathway-specific fi c alterations resulted in an overall enhancement of excitatory-to-spike coupling, a physiologically relevant index of how efficiently fi ciently excitatory inputs drive neuronal fi ring, in both BLA-+NAcC-D1-+ NAcC-D1 and BLA-+NAcC-D2-+ NAcC-D2 pathways. Finally, the absence of fragile X messenger ribonucleoprotein 1 (FMRP) led to impaired long-term depression specifically fi cally in BLA-+D1-+ 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, fi ciency, emphasizing its pivotal role in the pathophysiology of FXS.