Biology subjects

Tielemans, A.

Publications and source records attributed to Tielemans, A..

2 recordsLinked to original sources

bioRxiv2023

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

Parkinsons (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 Lrrk2 also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of AMPA-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we used Lrrk2G2019S knockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs to favor incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D1R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD. SIGNIFICANCE STATEMENTMutations in LRRK2 are common genetic risks for PD. Lrrk2G2019S mice fail to exhibit long-term potentiation at corticostriatal synapses and show significant deficits in frontal-striatal based cognitive tasks. While LRRK2 has been implicated generally in protein trafficking, whether G2019S derails AMPAR trafficking at synapses on striatal neurons (SPNs) is unknown. We show that surface GluA1-AMPARs fail to internalize and instead accumulate excessively within and outside synapses. This effect is selective to D1R SPNs and negatively impacts synapse strengthening as GluA1-AMPARs fail to increase at the surface in response to potentiation and show limited surface mobility. Thus, LRRK2-G2019S narrows the effective range of plasticity mechanisms, supporting the idea that cognitive symptoms reflect an imbalance in AMPAR trafficking mechanisms within cell-type specific projections.

neuroscience↗

bioRxiv2022

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

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.

neuroscience↗