Miquel-Rio LuisJericó-Escolar, JudithSarriés-Serrano, UnaiYanes-Castilla, ClaudiaTorres López, MaríaArgibay, UxiaBortolozzi, Analia2025-09-082025-09-082025-08-13Miquel-Rio Luis, , Jericó-Escolar, J., Sarriés-Serrano, U., Yanes-Castilla, C., Torres López, M., Argibay, U. y Bortolozzi, A. (2025). Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype. Npj Parkinson S Disease, 11 (1), 1.https://doi.org/10.1038/s41531-025-01073-1.2373-8057https://hdl.handle.net/11441/176789Anxiety and depression are common in Parkinson’s disease (PD), affecting quality of life. Aggregates of α-synuclein (α-Syn) are found in serotonergic (5-HT) raphe nuclei early in the disease, but their relationship to brain changes is unclear. We investigated synaptic plasticity, neuronal activity, and functional magnetic resonance imaging (fMRI)-based brain connectivity in a PD-like mouse model with depressive phenotype. AAV-induced human α-Syn accumulation in raphe 5-HT neurons causes progressive synaptic pathology in interconnected brain regions. This is marked by lower MAP-2, PSD95 and higher SV2A, VAMP2, which are key to synaptic structure and function, as confirmed in human brain tissue samples. Abnormalities in Egr-1-dependent neuronal activity and region-specific differences in resting-state functional brain activity were also detected eight weeks post-AAV infusion, before neurodegeneration. This provides evidence for synaptic and fMRI markers associated with α-Syn pathology in emotional brain circuits, and has translational importance for identifying PD patients at risk for depression.application/pdf18 p.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Early synapticBrain connectivityinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.1038/s41531-025-01073-1