Synaptic mechanisms underlying onset and progression of memory deficits caused by hippocampal and midbrain synucleinopathy
Attilio Iemolo, Maria De Risi, Nadia Giordano, Giulia Torromino, Cristina Somma, Diletta Cavezza, Martina Colucci, Maria Mancini, Antonio de Iure, R. Granata, Barbara Picconi, Paolo Calabresi, Elvira De Leonibus
Abstract
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.