Miquel-Rio, LluisJericó-Escolar, JudithSarriés-Serrano, UnaiYanes-Castilla, ClaudiaTorres-López, MaríaArgibay, UxiaPaz, VerónicaCasal, CarmenMuñoz-Moreno, EmmaLópez-Gil, XavierBortolozzi, Analía2025-11-242025-11-242025Miquel-Rio L, Jericó-Escolar J, Sarriés-Serrano U, Yanes-Castilla C, Torres-López M, Argibay U, et al. Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype. NPJ Parkinsons Dis. 2025;11(1):242. DOI: 10.1038/s41531-025-01073-12373-8057http://hdl.handle.net/10230/71970Anxiety 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/pdfengThis article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.MalaltiesNeurociènciesBiologia molecularinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41531-025-01073-1info:eu-repo/semantics/openAccess