α-Synuclein Selectively Impairs Motor Sequence Learning and Value Sensitivity: Reversal by the Adenosine A2A Receptor Antagonists

Abstract Parkinson’s disease (PD) is characterized pathologically by alpha-synuclein (α-Syn) aggregates and clinically by the motor as well as cognitive deficits, including impairments in sequence learning and habit learning. Using intracerebral injection of WT and A53T mutant α-Syn fibrils, we investigate the behavioral mechanism of α-Syn for procedure-learning deficit in PD by critically determining the α-Syn-induced effects on model-based goal-directed behavior, model-free (probability-based) habit learning, and hierarchically organized sequence learning. 1) Contrary to the widely held view of habit-learning deficit in early PD, α-Syn aggregates in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) did not affect acquisition of habit learning, but selectively impaired goal-directed behavior with reduced value sensitivity. 2) α-Syn in the DLS (but not DMS) and SNc selectively impaired the sequence learning by affecting sequence initiation with the reduced first-step accuracy. 3) Adenosine A2A receptor (A2AR) antagonist KW6002 selectively improved sequence learning by preferentially improving sequence initiation and shift of sequence learning as well as behavioral reactivity. These findings established a casual role of α-Syn in the SN-DLS pathway in sequence-learning deficit and DMS α-Syn in goal-directed behavior deficit and suggest a novel therapeutic strategy to improve sequence-learning deficit in PD with enhanced sequence initiation by A2AR antagonists.