Deficiency of Synaptotagmin 9 in the Hippocampal Region Induces Synaptic Damage and Cognitive Impairment in Parkinson's Disease Mice via BDNF/TrkB Signaling.

Cognitive impairment is a prominent non-motor symptom of Parkinson's disease (PD) that severely affects patients' quality of life, yet its underlying molecular mechanisms remain incompletely understood. Here, we investigated the role of hippocampal Synaptotagmin 9 (Syt9) in PD-related cognitive deficits. We found that Syt9 expression was significantly downregulated in the hippocampus of both MPTP-induced subacute PD mice and A53T α-synuclein transgenic mice, concomitant with cognitive impairment and synaptic damage. To determine causality, we performed hippocampal Syt9 knockdown and overexpression using AAV-mediated gene delivery. Syt9 knockdown exacerbated, while Syt9 overexpression alleviated, cognitive deficits and synaptic structural abnormalities in PD mice. Proteomic sequencing and pharmacological manipulations revealed that Syt9 may regulate the BDNF/TrkB signaling pathway at the protein level, likely by influencing BDNF vesicular transport, release, or stability. Intra-hippocampal BDNF supplementation rescued synaptic damage and cognitive impairment, whereas the TrkB antagonist ANA-12 reversed the protective effects of Syt9 overexpression. Collectively, our findings identify the Syt9/BDNF/TrkB axis as a key mechanism in PD-related cognitive impairment and suggest that targeting this pathway may offer a novel therapeutic strategy for PD.