Α-SYNUCLEIN ACCUMULATION IN THE MEDIAL PREFRONTAL CORTEX DRIVES ANXIETY-LIKE, COGNITIVE DEFICITS, AND SYNAPTIC REMODELING IN A MOUSE MODEL OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is a multisystem disorder, and although clinically characterized by motor symptoms, a wide range of disabling non-motor symptoms also occur throughout the course of the disease. Notably, neuropsychiatric symptoms, including anxiety and depression, affect up to 50% of individuals with PD, and cognitive decline is another common symptom, as well as being the main risk factor for the development of dementia. Although PD etiology remains unclear, abnormal accumulation of α-synuclein (α-Syn) across brain regions is a key pathological hallmark. Neuroimage and neuropathological studies suggests that α-synucleinopathy may originate in corticolimbic brain areas inducing synaptic degeneration and subsequent neuronal loss. Here, we investigated whether pathological α-Syn accumulation in the medial prefrontal cortex (mPFC) induces structural, cellular, and functional changes associated with non-motor PD symptoms. Female mice were bilaterally infused with AAV2/5-induced wild-type human α-Syn (h-α-Syn) expression or an AAV2/5-empty vector (control group) in the mPFC. Behavioral assessments revealed an anxiety-like phenotype and progressive spatial memory impairments in AAV2/5-h-α-Syn mice compared to controls. Immunofluorescence analyses showed time-dependent h-α-Syn and p-α-Syn accumulation in the mPFC and connected brain areas. Cellular profile showed alterations in distinct cell subtypes, including PV, SST and vGlut2-positive cells in the vmPFC. Additionally, morphological analyses revealed significant changes in dendritic spine density and maturity in AAV2/5-h-α-Syn mice. In conclusion, we show that selective α-Syn accumulation in the mPFC mimics the early neuropsychiatric and cognitive decline of PD. This model provides a valuable framework to unravel the synaptic mechanisms linking cortical pathology to non-motor symptoms.