Cognitive Deficits and Altered Cholinergic Innervation in Young Adult Mice Carrying a Parkinson's Disease LRRK2-G2019S Knockin Mutation

Abstract

Impaired executive function is a common and debilitating non-motor symptom of idiopathic and hereditary Parkinsons disease (PD), but there is little understanding of the underlying pathophysiological mechanisms and circuits. The G2019S mutation in the kinase domain of leucine-rich repeat kinase 2 (LRRK2) greatly increases risk for late-onset PD, and non-manifesting LRRK2-G2019S carriers also exhibit early and significant cognitive impairment. Here, we subjected young adult mice carrying a Lrrk2-G2019S knockin mutation to touchscreen-based operant tasks that measure attention, goal-directed learning and cognitive flexibility, all of which rely on prefrontal-striatal connectivity and are strongly modulated by cholinergic innervation. In a visuospatial attention task, mutant mice exhibited significantly more omissions and longer response latencies than controls that could not be attributed to deficits in motivation, visual sensory perception per se or locomotion, thereby suggesting impairment in divided attention and slower information processing speed. Pretreating mice with the acetylcholinesterase inhibitor donepezil normalized both higher omission rates and longer reward latencies in the mutants, but did not affect any performance metric in controls. Strikingly, cholinergic fiber density in mPFC and dorsomedial striatum was significantly sparser in mutants than in controls, while further behavioral interrogation of the mutants revealed significant impairments in action-outcome associations but preserved cognitive flexibility. These data suggest that the G2019S mutation impacts cholinergic innervation and impairs corticostriatal network function in young adulthood that may contribute to early PD-associated cognitive deficits. STATEMENT OF SIGNIFICANCEThe LRRK2-G2019S mutation causes hereditary Parkinsons disease and is found in some idiopathic cases. Early cognitive impairment is a common symptom of hereditary and idiopathic PD, yet there is little mechanistic understanding of such impairment. Here, we tested young adult Lrrk2-G2019S knockin mice in a series of touchscreen-based visuospatial tasks. We found that mutants exhibited significant deficits in attention and goal-directed learning, and had significantly slower information processing speed. Treatment with an acetylcholinesterase inhibitor reversed some of these behavioral deficits, while anatomical analyses showed significantly sparser cholinergic innervation of brain structures important for executive function. These findings suggest the G2019S mutation alters cholinergic signaling in young adulthood, and thus may contribute to early PD-associated impairment in several cognitive domains.