Cell- and Pathway-Specific Disruptions in the Accumbens of Fragile X Mouse.
J Neurosci
; 44(30)2024 Jul 24.
Article
in En
| MEDLINE
| ID: mdl-38830765
ABSTRACT
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 BLAâNAcC, PFCâNAcC, and reciprocal PFCâBLA pathways in Fmr1-/yDrd1a-tdTomato male mice. In FXS mice, the PFCâBLA reciprocal pathway was unaffected, while significant synaptic modifications occurred in the BLA/PFCâNAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications in D2 SPNs. In FXS mice, the BLA/PFCâNAcC-D2 SPN pathways demonstrated heightened synaptic strength. Focusing on the BLAâNAcC 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 BLAâNAcC-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 BLAâNAcC-D1 and BLAâNAcC-D2 pathways. Finally, the absence of fragile X messenger ribonucleoprotein 1 (FMRP) led to impaired long-term depression specifically in BLAâD1 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fragile X Mental Retardation Protein
/
Fragile X Syndrome
/
Nucleus Accumbens
Limits:
Animals
Language:
En
Journal:
J Neurosci
Year:
2024
Type:
Article
Affiliation country:
France