Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype

Bortolozzi, A.; Miquel Rio, L.; Jerico-Escolar, J.; Sarries-Serrano, U.; Yanes-Castilla, C.; Paz, V.; Torres-Lopez, M.; Argibay, U.; Munoz, E.; Lopez-Gil, X.

doi:10.1101/2025.04.24.650442

bioRxiv · 10.1101/2025.04.24.650442

Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype

Bortolozzi, A.·Miquel Rio, L.·Jerico-Escolar, J.·Sarries-Serrano, U.·Yanes-Castilla, C.·Paz, V.·Torres-Lopez, M.·Argibay, U.·Munoz, E.·Lopez-Gil, X.

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Abstract

Anxiety and depression are common in Parkinsons disease (PD), affecting quality of life. Aggregates of -synuclein (-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 -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 -Syn pathology in emotional brain circuits, and has translational importance for identifying PD patients at risk for depression.

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Bortolozzi, A., Miquel Rio, L., Jerico-Escolar, J., Sarries-Serrano, U., Yanes-Castilla, C., Paz, V., Torres-Lopez, M., Argibay, U., Munoz, E., Lopez-Gil, X.. 2025-04-24. Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype. https://doi.org/10.1101/2025.04.24.650442

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