Hussein A, Tielemans A, Baxter MG, Benson DL, Huntley GW. Cognitive deficits and altered cholinergic innervation in young adult male mice carrying a Parkinson’s disease Lrrk2-G2019S knockin mutation. Exp Neurology (2022) doi: 10.1016/j.expneurol.2022.114145.

Deficits in attention and slower information processing speed are common and early-appearing cognitive abnormalities of idiopathic and hereditary Parkinson’s disease (PD). To explore the underlying neurobiology of such cognitive impairment, we interrogated mice carrying a G2019S knockin mutation in the kinase domain of leucine-rich repeat kinase 2 (LRRK2)—a mutation which in humans greatly increases risk for late-onset PD—behaviorally, pharmacologically and anatomically. Young adult male Lrrk2^G2019S  and wildtype control mice were subjected to a 5-Choice Serial Reaction Time task–a touchscreen-based attention task that relies on frontal-striatal connectivity and is strongly modulated by cholinergic innervation. 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 impairments in divided attention and/or action-selection as well as generally slower information processing speed. Pretreating mice with the acetylcholinesterase inhibitor donepezil normalized both higher omission rates and longer response latencies in the mutants, but did not affect any performance metric in controls. We found further that cholinergic fiber density in cortical areas PL/IL was significantly sparser in mutants than in controls. These data suggest that the Lrrk2^G2019S mutation negatively impacts cholinergic innervation anatomically and functionally by young adulthood, impairing corticostriatal network function in ways that may contribute to early PD-associated executive function deficits.