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Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex.

ABSTRACT: The two principal movement-suppressing pathways of the basal ganglia, the so-called hyperdirect and indirect pathways, interact within the subthalamic nucleus (STN). An appropriate level and pattern of hyperdirect pathway cortical excitation and indirect pathway external globus pallidus (GPe) inhibition of the STN are critical for normal movement and are greatly perturbed in Parkinson's disease. Here we demonstrate that motor cortical inputs to the STN heterosynaptically regulate, through activation of postsynaptic NMDA receptors, the number of functional GABAA receptor-mediated GPe-STN inputs. Therefore, a homeostatic mechanism, intrinsic to the STN, balances cortical excitation by adjusting the strength of GPe inhibition. However, following the loss of dopamine, excessive cortical activation of STN NMDA receptors triggers GPe-STN inputs to strengthen abnormally, contributing to the emergence of pathological, correlated activity.

SUBMITTER: Chu HY

PROVIDER: S-EPMC4304914 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex.

Chu Hong-Yuan HY Atherton Jeremy F JF Wokosin David D Surmeier D James DJ Bevan Mark D MD

Neuron 20150108 2

The two principal movement-suppressing pathways of the basal ganglia, the so-called hyperdirect and indirect pathways, interact within the subthalamic nucleus (STN). An appropriate level and pattern of hyperdirect pathway cortical excitation and indirect pathway external globus pallidus (GPe) inhibition of the STN are critical for normal movement and are greatly perturbed in Parkinson's disease. Here we demonstrate that motor cortical inputs to the STN heterosynaptically regulate, through activa ...[more]

PMID: 25578364

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Project description:Key pointsReciprocally 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, and (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.AbstractReciprocally 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 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 anaesthesia 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, and (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.

Dataset Information

Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex.

Publications

Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex.

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