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The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

ABSTRACT: The dynamical properties of cortico-basal ganglia (CBG) circuits are dramatically altered following the loss of dopamine in Parkinson's disease (PD). The neural circuit dysfunctions associated with PD include spike-rate alteration concomitant with excessive oscillatory spike-synchronization in the beta frequency range (12-30?Hz). Which neuronal circuits orchestrate and propagate these abnormal neural dynamics in CBG remains unknown. In this work, we combine in vivo electrophysiological recordings with advanced optogenetic manipulations in normal and 6-OHDA rats to shed light on the mechanistic principle underlying circuit dysfunction in PD. Our results show that abnormal neural dynamics present in a rat model of PD do not rely on cortical or subthalamic nucleus activity but critically dependent on globus pallidus (GP) integrity. Our findings highlight the pivotal role played by the GP which operates as a hub nucleus capable of orchestrating firing rate and synchronization changes across CBG circuits both in normal and pathological conditions.

SUBMITTER: Crompe B

PROVIDER: S-EPMC7099038 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

Crompe Brice de la B Aristieta Asier A Leblois Arthur A Elsherbiny Salma S Boraud Thomas T Mallet Nicolas P NP

Nature communications 20200326 1

The dynamical properties of cortico-basal ganglia (CBG) circuits are dramatically altered following the loss of dopamine in Parkinson's disease (PD). The neural circuit dysfunctions associated with PD include spike-rate alteration concomitant with excessive oscillatory spike-synchronization in the beta frequency range (12-30 Hz). Which neuronal circuits orchestrate and propagate these abnormal neural dynamics in CBG remains unknown. In this work, we combine in vivo electrophysiological recording ...[more]

PMID: 32218441

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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.

Project description:BackgroundFragile X premutation carriers (55-200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle-the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown.MethodsWe estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8-86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus.ResultsAmong participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus.ConclusionsOnly the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occurrence of combined MCP and pallidal T2-abnormalities may present a risk for greater cognitive impairment and increased iron variability in the globus pallidus.

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The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

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The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

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