Dysregulation of external globus pallidus‐subthalamic nucleus network dynamics in parkinsonian mice during cortical slow‐wave activity and activation
J Physiol. 2020-02-29; :
DOI: 10.1113/JP279232
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Kovaleski RF(1), Callahan JW(1), Chazalon M(2), Wokosin DL(1), Baufreton J(2), Bevan MD(1).
Author information:
(1)Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60602.
(2)Université de Bordeaux & CNRS UMR 5293, Institut des Maladies Neurodégénératives, Bordeaux, F-33000, France.
KEY POINTS: Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia. In Parkinson’s disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell
class-specific optogenetic identification and inhibition during cortical slow-wave activity and activation, we report that in dopamine-depleted mice 1) D2
dopamine receptor expressing striatal projection neurons (D2-SPNs) discharge at higher rates, especially during cortical activation 2) prototypic
parvalbumin-expressing GPe neurons are excessively patterned by D2-SPNs even though their autonomous activity is upregulated 3) despite being disinhibited,
STN neurons are not hyperactive 4) STN activity opposes striatopallidal patterning. These data argue that in parkinsonian mice, abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment.
ABSTRACT: Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally-positioned network within the basal ganglia. In Parkinson’s disease (PD) and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Following the loss of dopamine, the activities of GPe and STN neurons become more temporally offset and strongly correlated with cortical
oscillations below 40 Hz. Previous studies utilized cortical slow-wave activity and/or cortical activation (ACT) under anesthesia to probe the mechanisms
underlying the normal and pathological patterning of basal ganglia activity. Here, we combined this approach with in vivo optogenetic inhibition to identify
and interrupt the activity of D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs), parvalbumin-expressing prototypic GPe (PV GPe) neurons, and STN neurons. We found that in dopamine-depleted mice 1) the firing rate of D2-SPNs was elevated, especially during cortical ACT 2) abnormal phasic
suppression of PV GPe neuron activity was ameliorated by optogenetic inhibition of coincident D2-SPN activity 3) autonomous PV GPe neuron firing ex vivo was
upregulated, presumably through homeostatic mechanisms 4) STN neurons were not hyperactive, despite being disinhibited 5) optogenetic inhibition of the STN
exacerbated abnormal GPe activity 6) exaggerated beta band activity was not present in the cortex or GPe-STN network. Together with recent studies, these
data suggest that in dopamine-depleted mice, abnormally correlated and temporally offset PV GPe and STN neuron activity is generated in part by elevated
striatopallidal transmission, while compensatory plasticity prevents STN hyperactivity and limits cortical entrainment.