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Thesis

French

ID: <

10670/1.b7jzkz

>

Where these data come from
Involvement of striatal cholinergic interneurons in the pathophysiology of Parkinson's disease : optogenetics, pharmacological and behavioral approaches

Abstract

Parkinson’s disease (PD) is characterized by a dopamiergic loss into the striatum, a subcortical structure involved in motor control, memory and emotional behaviors. Striatal cholinergic interneurons (ChIs) play a key role in this pathological reorganization of the striatal circuitry by modulating striatal projection neurons (MSNs). This study aims to investigate the involvement of ChIs and muscarinic receptors (mAChRs) in the mechanisms underlying the expression of motor, cognitive and emotional deficits observed in different models of PD in mice. ChIs optogenetic inhibition reduced motor deficits (akinesia, postural asymmetry, sensorimotor deficit). Electrophysiological recordings show that ChIs photoinhibition reduces MSNs excitability and restores the balance between the two striatal output pathways. These antiparkinsonian effects are reproduced by pharmacological intrastriatal blockade of M1 and M4 mAChRs. They are due to a preferential action of ACh on mAChRs expressed on striatonigral MSNs since the deficits disappear in mutant mice that lack M4 mAChRs only in these neurons. ChIs photoinhibition also reduces memory deficits and anxiety. M1 mAChRs antagonist reduces anxiety but is inefficient on memory deficits, suggesting that other cholinergic receptors might be involved in striatal memory functions. Overall, these results give new insights on the role of cholinergic interneurons in the normal and pathological functioning of the striatum.

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