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bioRxiv · 10.1101/385443

Chemogenetic restoration of autonomous subthalamic nucleus activity ameliorates Parkinsonian motor dysfunction

McIver, E. L.·Chu, H.-Y.·Atherton, J. F.·Cosgrove, K. E.·Kondapalli, J.·Wokosin, D.·Surmeier, D. J.·Bevan, M. D.
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Abstract

HighlightsO_LIdecorrelating autonomous STN activity was downregulated in both toxin and genetic models of PD\nC_LIO_LIelevation of D2-striatal projection neuron transmission was sufficient for downregulation\nC_LIO_LIdownregulation was dependent on activation of STN NMDA receptors and KATP channels\nC_LIO_LIchemogenetic restoration of autonomous spiking reduced synaptic patterning of STN neurons and PD motor dysfunction\nC_LI\n\neToCExcessive synaptic synchronization of STN activity is linked to the symptomatic expression of PD.McIver and colleagues describe the cellular and circuit mechanisms responsible for the loss of decorrelating autonomous STN activity in PD models and demonstrate that chemogenetic rescue of autonomous spiking reduces synaptically patterned STN activity and ameliorates Parkinsonian motor dysfunction.\n\nSUMMARYExcessive, synaptically-driven synchronization of subthalamic nucleus (STN) neurons is widely thought to contribute to akinesia, bradykinesia, and rigidity in Parkinsons disease (PD). Electrophysiological, optogenetic, chemogenetic, genetic, 2-photon imaging, and pharmacological approaches revealed that the autonomous activity of STN neurons, which opposes synaptic synchronization, was downregulated in both toxin and genetic mouse models of PD.Loss of autonomous spiking was due to increased transmission of D2-striatal projection neurons, leading in the STN to elevated activation of NMDA receptors and generation of reactive oxygen species that promoted KATP channel opening.Chemogenetic restoration of autonomous firing in STN neurons reduced synaptic patterning and ameliorated Parkinsonian motor dysfunction, arguing that elevating intrinsic STN activity is an effective therapeutic intervention in PD.

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McIver, E. L., Chu, H.-Y., Atherton, J. F., Cosgrove, K. E., Kondapalli, J., Wokosin, D., Surmeier, D. J., Bevan, M. D.. 2018-08-16. Chemogenetic restoration of autonomous subthalamic nucleus activity ameliorates Parkinsonian motor dysfunction. https://doi.org/10.1101/385443

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