Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility, and composition in striatum with cell-type and subunit specificity.

Parkinson's disease (PD) is a multifactorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal-based cognitive function are common, appear early, and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation in also exhibit deficits in fronto-striatal-based cognitive tasks.

Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility and composition in striatum with cell-type and subunit specificity.

Unlabelled: Parkinson's (PD) is a multi-factorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal based cognitive function are common, appear early and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation in also exhibit deficits in fronto-striatal-based cognitive tasks.

Cognitive deficits and altered cholinergic innervation in young adult male mice carrying a Parkinson's disease Lrrk2 knockin mutation.

Impaired executive function is a common and debilitating non-motor symptom of idiopathic and hereditary Parkinson's 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 carriers can also exhibit early and significant cognitive impairment. Here, we subjected young adult male mice carrying a Lrrk2 knockin mutation to touchscreen-based operant tasks that measure attention, goal-directed learning and cognitive flexibility, all of which rely on frontal-striatal connectivity and are strongly modulated by cholinergic innervation.