Synaptic mechanisms underlying onset and progression of memory deficits caused by hippocampal and midbrain synucleinopathy

Authors: Attilio Iemolo, Maria De Risi, Nadia Giordano, Giulia Torromino, Cristina Somma, Diletta Cavezza, Martina Colucci, Maria Mancini, Antonio de Iure, Rocco Granata, Barbara Picconi, Paolo Calabresi & Elvira De Leonibus
Year: 2023
Sources: NPJ Parkinson's DIsease
Cognitive deficits, including working memory, and visuospatial deficits are common and debilitating in Parkinson’s disease. α-synucleinopathy in the hippocampus and cortex is considered as the major risk factor. However, little is known about the progression and specific synaptic mechanisms underlying the memory deficits induced by α-synucleinopathy. Here, we tested the hypothesis that pathologic α-Synuclein (α-Syn), initiated in different brain regions, leads to distinct onset and progression of the pathology. We report that overexpression of human α-Syn in the murine mesencephalon leads to late onset memory impairment and sensorimotor deficits accompanied by reduced dopamine D1 expression in the hippocampus. In contrast, human α-Syn overexpression in the hippocampus leads to early memory impairment, altered synaptic transmission and plasticity, and decreased expression of GluA1 AMPA-type glutamate receptors. These findings identify the synaptic mechanisms leading to memory impairment induced by hippocampal α-synucleinopathy and provide functional evidence of the major neuronal networks involved in disease progression.
Category: journals