title: Desynchronization of fast-spiking interneurons reduces β-band oscillations and imbalance in firing in the dopamine-depleted striatum.
abstract: Oscillations in the β-band (8-30 Hz) that emerge in the output nuclei of the basal ganglia during Parkinson's disease, along with an imbalanced activation of the direct and indirect pathways, have been linked to the hypokinetic motor output associated with the disease. Although dopamine depletion causes a change in cellular and network properties in the striatum, it is unclear whether abnormal activity measured in the globus pallidus and substantia nigra pars reticulata is caused by abnormal striatal activity. Here we use a computational network model of medium spiny neurons (MSNs)-fast-spiking interneurons (FSIs), based on data from several mammalian species, and find that robust β-band oscillations and imbalanced firing emerge from implementation of changes to cellular and circuit properties caused by dopamine depletion. These changes include a reduction in connections between MSNs, a doubling of FSI inhibition to D2 MSNs, an increase in D2 MSN dendritic excitability, and a reduction in D2 MSN somatic excitability. The model reveals that the reduced decorrelation between MSNs attributable to weakened lateral inhibition enables the strong influence of synchronous FSIs on MSN firing and oscillations. Weakened lateral inhibition also produces an increased sensitivity of MSN output to cortical correlation, a condition relevant to the parkinsonian striatum. The oscillations of FSIs, in turn, are strongly modulated by fast electrical transmission between FSIs through gap junctions. These results suggest that pharmaceuticals that desynchronize FSI activity may provide a novel treatment for the enhanced β-band oscillations, imbalanced firing, and motor dysfunction in Parkinson's disease.
authors.affiliation: Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030.
authors.forename: Sriraman
authors.initials: S
authors.lastname: Damodaran
authors.affiliation: Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030.
authors.forename: John R
authors.identifier: http://orcid.org/0000-0003-3621-2075
authors.initials: JR
authors.lastname: Cressman
authors.affiliation: Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030.
authors.forename: Zbigniew
authors.identifier: http://orcid.org/0000-0002-6548-7951
authors.initials: Z
authors.lastname: Jedrzejewski-Szmek
authors.affiliation: Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030 kblackw1@gmu.edu.
authors.forename: Kim T
authors.identifier: http://orcid.org/0000-0003-4711-2344
authors.initials: KT
authors.lastname: Blackwell
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D001611:Beta Rhythm / Q000502:physiology*; D003198:Computer Simulation; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism*; D007395:Interneurons / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology
chemical_list: D004298:Dopamine
keywords: Parkinson's disease; beta-band oscillation; fast-spiking interneurons; gap junctions; striatal imbalance; striatum