Proliferation of Inhibitory Input to the Substantia Nigra in Experimental Parkinsonism

Abstract

The substantia nigra pars reticulata (SNr) is one of the output nuclei of the basal ganglia (BG) and plays a vital role in movement execution. Death of dopaminergic neurons in the neighboring nucleus, the substantia nigra pars compacta (SNc), leads to Parkinson's disease. The ensuing dopamine depletion affects all BG nuclei. However, the long-term effects of dopamine depletion on BG output are less characterized. In this in vitro study, we applied electrophysiological and immunohistochemical techniques to investigate the long-term effects of dopamine depletion on GABAergic transmission to the SNr. The findings showed a reduction in firing rate and regularity in SNr neurons after unilateral dopamine depletion with 6-OHDA, which we associate with homeostatic mechanisms. The strength of the GABAergic synapses between the globus pallidus (GP) and the SNr increased but not their short-term dynamics. Consistent with this observation, there was an increase in the frequency and amplitude of spontaneous inhibitory synaptic events to SNr neurons. Immunohistochemistry revealed an increase in the density of vGAT-labeled puncta in dopamine depleted animals. Overall, these results may suggest that synaptic proliferation can explain how dopamine depletion augments GABAergic transmission in the SNr.

Mass Spectrometry–Based Proteomics Analysis of Human Substantia Nigra From Parkinson's Disease Patients Identifies Multiple Pathways Potentially Involved in the Disease

“…For example, although SN does not have GABAergic neurons, the SN pars reticulata (SNr) region has receptors for GABAergic projection exons ( 64 ). It is known that DA depletion induced by dopaminergic neuronal death in SN pars compacta (SNc) of PD patients affects GABAergic transmission in basal ganglia and this, in turn, possibly affected the expression of GABAergic receptors in SNr ( 65 ). Therefore, dysregulation of GABA receptor proteins in the SN of PD could be considered a consequence of dopaminergic neuronal death.…”

Apoptotic factors and mitochondrial complexes assist determination of strain-specific susceptibility of mice to Parkinsonian neurotoxin MPTP

“…α-Synuclein being a synaptic protein, aberrant synaptic plasticity in SNpr, may contribute to pathophysiology of PD (Prescott et al, 2009). Faynveitz et al, (2019) demonstrated that 6-OHDA-induced depletion of dopamine in the SNpc neurons, results in reduced firing rate and periodicity of the SNr neurons, suggesting expansion of GABAergic inhibition within the SNr, and thus contributing to PD pathology.…”

Identification of Potential Core Genes in Parkinson’s Disease Using Bioinformatics Analysis

“…PD is well known to be caused by the progressive death of DA neurons in the substantia nigra of the midbrain, leading to a lack of DA in the striatum. Studies have shown that chronic DA depletion can enhance the transmission of GABA in the striatum, thus affecting cell and circuit activities, which are related to the pathogenesis of PD [ 40 ]. A study has shown [ 41 ] that patients with PD in Braak 3 exhibit an increased threshold of GABA medium spiny neurons, and patients with PD in Braak 4 exhibit decreased spontaneous GABA activity.…”