ELECTROPHYSIOLOGICAL CHARACTERIZATION OF THE LOCUS COERULEUS NETWORK IN A RODENT MODEL OF PRODROMAL PARKINSON’S DISEASE

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder associated with non-motor symptoms that often emerge during prodromal stages. The locus coeruleus (LC), the main noradrenergic nucleus of the brain, is among the regions affected early, and its dysfunction and α-synuclein (α-syn)-associated pathology have been linked to early emotional and cognitive disturbances. Despite being small, the LC contains distinct neuronal subpopulations that project to specific brain regions, including the amygdala and the hippocampus (HP), which play key roles in emotional processing and cognition, respectively. However, the functional impact of early α-syn pathology on specific LC-limbic circuits remains unknown. In this study, we investigated whether α-syn overexpression in the LC alters the electrophysiological properties of noradrenergic LC neurons projecting to the central amygdala (CeA) and HP, as potential early mechanisms underlying non-motor symptoms in PD. Using a prodromal PD mouse model with viral-mediated human α-syn overexpression in the LC, LC-CeA and LC-HP neurons were retrogradely labeled with retrobeads injected into their respective target regions. Ex vivo electrophysiological recordings were performed in brainstem slices to assess intrinsic membrane properties and neuronal excitability in these projection-defined LC neurons. Preliminary results reveal subtle alterations in electrophysiological properties of LC-CeA and LC-HP neurons in α-syn–overexpressing mice, with potential sex-dependent and projection-specific differences. These findings suggest that α-syn accumulation may selectively affect specific LC neuronal subpopulations, supporting the hypothesis that early circuit-level dysfunction contributes to the emergence of emotional and cognitive non-motor symptoms during initial stages of PD.