Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms (original) (raw)
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Neuroscience, 2005
The therapeutic effect of STN lesion in PD is classically ascribed to the rescue of physiological activity in the output structures of the basal ganglia, and little is known about the possible involvement of the striatum. In the present study, therefore, we electrophysiologically recorded in vitro single striatal neurons of DA-depleted rats unilaterally lesioned by 6-hydroxydopamine, treated or not with therapeutic doses of levodopa (L-DOPA), or with a consecutive ipsilateral STN lesion. We show that the beneficial motor effects produced in parkinsonian rats by STN lesion or L-DOPA therapy were paralleled by the normalization of overactive frequency and amplitude of striatal glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Since neither L-DOPA treatment nor STN lesion affected sEPSCs kinetic properties, the reversal of these abnormalities in striatal excitatory synaptic transmission can be attributable to the normalization of glutamate release. © 2005 Published by Elsevier Ltd on behalf of IBRO.
European Journal of Neuroscience, 2006
Hyperactivity of striatal glutamatergic synaptic transmission in response to dopamine depletion plays a major role in the pathogenesis of parkinsonian motor symptoms. In the present study we investigated the impact, on this hyperactivity, of chronic dyskinesiogenic L-DOPA treatment, combined or not with high-frequency stimulation (HFS) of the subthalamic nucleus (STN). In vitro patch-clamp recordings were performed from striatal spiny neurons of hemiparkinsonian rats (intranigral 6-OHDA injection). Here we show that dyskinesiogenic L-DOPA treatment exacerbated striatal glutamatergic hyperactivity induced by 6-OHDA lesion. Chronic 5-day STN HFS had the opposite effect, reducing striatal glutamatergic transmission in both parkinsonian and dyskinetic animals. Consistently, chronic HFS stimulation could progressively ameliorate motor parkinsonian signs (akinesia) but, conversely, did not improve L-DOPA-induced dyskinesia (LID). Thus, the effects of L-DOPA and HFS on corticostriatal transmission seem to be dissociated. These data show for the first time that dyskinesiogenic L-DOPA treatment and chronic STN HFS with antiakinetic effects induce opposite plastic rearrangements in the striatum. The interaction between these two treatments provides further evidence that striatal glutamatergic hyperactivity is a pathophysiological correlate of akinesia rather than LID.
Mild dopaminergic lesions are accompanied by robust changes in subthalamic nucleus activity
Neuroscience Letters, 2012
The subthalamic nucleus (STN) is a major player in the input and output of the basal ganglia motor circuitry. The neuronal regular firing pattern of the STN changes into a pathological bursting mode in both advanced Parkinson's disease (PD) and in PD animals models with severe dopamine depletion. One of the current hypothesis, based on clinical and experimental evidence, is that this typical burst activity is responsible for some of the principal motor symptoms. In the current study we tested whether mild DA depletion, mimicking early stages of PD, induced deficits in motor behaviour and changes in STN neuronal activity. The present study demonstrated that rats with a mild lesion (20-40% loss of DA neurons) and a slowed motor response, but without gross motor abnormalities already have an increased number of bursty STN neurons under urethane anaesthesia. These findings indicate that the early increase in STN burst activity is a compensatory mechanism to maintain the dopamine homeostasis in the basal ganglia.
Journal of Neurosurgery, 2006
Object The purpose of this study was to determine whether subthalamic nucleus (STN) ablation caused by kainic acid can restore dopaminergic neurotransmission and improve motor deficits in a 6-hydroxydopamine (6-OHDA)–induced hemiparkinsonian model. Methods The authors investigated behavioral changes in rats displaying parkinsonian symptoms (6-OHDA–lesioned rats) after an STN lesion was created using kainic acid. They also measured levels of dopamine and its metabolites following tissue dissection. The results of this study showed that STN ablation led to behavioral improvement in parkinsonian motor deficits. Increased levels of dopamine were also observed in the striatum and globus pallidus externus (GPE). Conclusions The results indicate that creation of an STN lesion in this hemiparkinsonian rat model may counteract some of the neurochemical changes within the striatum and GPE caused by the 6-OHDA, and influence striatal dopaminergic metabolism.
The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism
Journal of Neurophysiology, 1994
1. The neuronal mechanisms underlying the major motor signs of Parkinson's disease were studied in the basal ganglia of parkinsonian monkeys. Three African green monkeys were systemically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until parkinsonian signs, including akinesia, rigidity, and a prominent 4- to 8-Hz tremor, appeared. The activity of neurons in the subthalamic nucleus (STN) and in the internal segment of the globus pallidus (GPi) was recorded before (STN, n = 220 cells; GPi, n = 175 cells) and after MPTP treatment (STN, n = 326 cells; GPi, n = 154 cells). 2. In STN the spontaneous firing rate was significantly increased from 19 +/- 10 (SD) spikes/s before to 26 +/- 15 spikes/s after MPTP treatment. Division of STN neurons recorded after MPTP treatment into cells with rhythmic bursts of discharge occurring at 4–8 Hz (as defined by autocorrelation analysis) and neurons without 4- to 8-Hz periodic activity revealed an even more prominent increase i...
Cell Reports, 2019
Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson's disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice. Loss of autonomous spiking in PD mice is prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown and reversed by reactive oxygen species breakdown or K ATP channel inhibition. Chemogenetic activation of hM3D(Gq) in STN neurons in Parkinsonian mice rescues their intrinsic activity, modifies their synaptic integration, and ameliorates motor dysfunction. Together these data argue that in PD mice increased indirect pathway activity leads to disinhibition of the STN, which triggers maladaptive NMDAR-dependent downregulation of autonomous firing.
The Journal of Comparative Neurology, 2000
The existence of a dopaminergic innervation of the subthalamic nucleus (STN) has been demonstrated in rats but has remained controversial in primates. The aim of the present study was first to demonstrate the existence of a dopaminergic innervation of the STN in monkeys using tracing methods and then to quantify the loss of dopaminergic fibers in the parkinsonian state in monkeys and humans. Following injection of Fluoro-Gold into the STN of a vervet monkey (Cercopithecus aethiops), retrogradely labeled neurons were found to be scattered in all dopaminergic areas of the mesencephalon. Injection of biotin dextran amine into dopaminergic areas A8 and A9 of two monkeys resulted in anterogradely labeled axons located throughout the whole extent of the STN. Labeled axons that also expressed tyrosine hydroxylase (TH) were reconstructed from serial sections. Some terminal axonal arborizations had profuse branching and occupied much of the STN, and others were restricted to small portions of the nucleus. In TH-immunoreactive sections, numerous sparse, fine, and varicose TH-positive fibers were observed in the STN of normal monkeys and humans. Quantification of these TH-positive fibers revealed a 51% loss of TH-positive fibers in MPTP-intoxicated monkeys and a 65% loss in Parkinson's disease patients compared with their respective controls. These findings demonstrate the existence of a dopaminergic innervation of the STN in primates. The loss of dopaminergic innervation in MPTP-intoxicated monkeys and in Parkinson's disease patients may directly affect the activity of STN neurons and could participate in the hyperactivity of the structure.