SEROTONERGIC Α-SYNUCLEINOPATHY DISRUPTS VMPFC–RAPHE CIRCUIT ACTIVITY AND CONNECTIVITY, PROMOTING AN ANXIETY-LIKE PHENOTYPE IN FEMALE MICE

Parkinson’s disease (PD) is characterized by motor dysfunction, but non-motor symptoms often precede motor onset and contribute to disease burden. Depression and anxiety are the most prevalent non-motor manifestations and are more severe in women. Serotonergic (5-HT) dysfunction is a well-established risk factor for mood disorders. We used a female mouse model of 5-HT α-synucleinopathy, generated by AAV1/2-mediated overexpression of A53T human α-synuclein (h-α-Syn) in the raphe nuclei, to investigate the role of the ventromedial prefrontal cortex–dorsal raphe (vmPFC–DR) circuit in neuropsychiatric symptoms. Animals were assessed at 4 and 8 weeks post-h-α-Syn overexpression. The anxious/depressive phenotype was evaluated through a battery of behavioural tests. Neuronal activity in the infralimbic (IL) and prelimbic (PL) cortices was recorded in awake, head-fixed mice using a multichannel probe in a virtual reality corridor. Functional and structural connectivity was assessed by functional magnetic resonance imaging (fMRI). Synaptic markers in the vmPFC were also evaluated. Female mice overexpressing h-α-Syn in 5-HT neurons developed a anxiety-like phenotype. This was accompanied by disrupted firing dynamics and functional organization of the vmPFC–DR circuit, including altered firing rates of PL and IL neurons, impaired connectivity, and changes in synaptic markers in the PFC. Notably, ketamine treatment partially reversed both the anxiety-like behaviour and the associated neural and synaptic alterations. Overall, h-α-Syn overexpression in DR 5-HT neurons induces vmPFC–DR circuit dysfunction and anxiety-like behaviours in female mice. Work supported by: MCIU/AEI/FEDER, UE grant (PID2022- 141700OB-I00,), AGAUR 2021-SGR-01358 Catalonia Government and 2023 BBRF Young Investigator Grant 31547