INTRODUCTION: Synucleinopathies, including Parkinson's disease (PD) and Lewy body dementia (LBD), are characterized by misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies, a key pathological hallmark. These disorders display region-specific vulnerability, with PD affecting the nigrostriatal dopaminergic system and LBD involving the neocortex. However, the molecular basis of selective vulnerability, particularly hippocampal involvement, remains poorly understood. OBJECTIVES: We aimed to determine whether the G2-3 α-synuclein transgenic mouse model recapitulates region-specific vulnerabilities observed in human synucleinopathies and to identify molecular and cellular mechanisms underlying region-specific pathology. METHODS: Six-month-old G2-3 mice and wild-type (WT) littermates underwent spatial transcriptomics profiling, followed by Gene Ontology (GO) and KEGG enrichment analyses. Key findings were validated using immunohistochemistry and cell-type deconvolution. RESULTS: Spatial transcriptomics revealed region-specific transcriptomic alterations in the G2-3 synucleinopathy mouse brain, with the hippocampus-particularly the DG and CA subfields-showing the most pronounced changes. GO analysis highlighted enrichment of synapse-related processes, and immunohistochemistry confirmed reduced and mislocalized PSD95 with glial colocalization. KEGG analysis further identified MAPK signaling activation, validated by increased neuronal p-ERK, underscoring hippocampus-specific molecular and structural vulnerabilities under α-syn pathology. CONCLUSION: Our study demonstrates that the hippocampus is a selectively vulnerable region in the G2-3 synucleinopathy mouse model, showing both transcriptional and structural synaptic alterations. Spatial transcriptomics revealed hippocampal enrichment of synapse-related processes and MAPK signaling, which were corroborated by immunohistochemical evidence of PSD95 mislocalization and neuronal p-ERK activation. These results provide mechanistic insights into hippocampal vulnerability and highlight spatial transcriptomics as a powerful tool to uncover region-specific disease mechanisms in synucleinopathies.