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Parkin deficiency perturbs striatal circuit dynamics.

Abstract：

:Loss-of-function mutations in the parkin-encoding PARK2 gene are a frequent cause of young-onset, autosomal recessive Parkinson's disease (PD). Parkin knockout mice have no nigro-striatal neuronal loss but exhibit abnormalities of striatal dopamine transmission and cortico-striatal synaptic function. How these predegenerative changes observed in vitro affect neural dynamics at the intact circuit level, however, remains hitherto elusive. Here, we recorded from motor cortex, striatum and globus pallidus (GP) of anesthetized parkin-deficient mice to assess cortex-basal ganglia circuit dynamics and to dissect cell type-specific functional connectivity in the presymptomatic phase of genetic PD. While ongoing activity of presumed striatal spiny projection neurons and their downstream counterparts in the GP was not different from controls, parkin deficiency had a differential impact on striatal interneurons: In parkin-mutant mice, tonically active neurons displayed elevated activity levels. Baseline firing rates of transgenic striatal fast spiking interneurons (FSI), on the contrary, were reduced and the correlational structure of the FSI microcircuitry was disrupted. The entire transgenic striatal microcircuit showed enhanced and phase-shifted phase coupling to slow (1-3 Hz) cortical population oscillations. Unexpectedly, local field potentials recorded from striatum and GP of parkin-mutant mice robustly displayed amplified beta oscillations (~22 Hz), phase-coupled to cortex. Parkin deficiency selectively increased spike-field coupling of FSIs to beta oscillations. Our findings suggest that loss of parkin function leads to amplifications of synchronized cortico-striatal oscillations and an intrastriatal reconfiguration of interneuronal circuits. This presymptomatic disarrangement of dynamic functional connectivity may precede nigro-striatal neurodegeneration and predispose to imbalance of striatal outflow accompanying symptomatic PD.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

Baaske MK,Kramer ER,Meka DP,Engler G,Engel AK,Moll CKE

doi

10.1016/j.nbd.2020.104737

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

104737

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(20)30012-7

journal_volume

137

pub_type

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Parkin deficiency perturbs striatal circuit dynamics.