Alteration of GABAergic neurotransmission in Huntington's disease

Abstract

Hereditary Huntington's disease (HD) is characterized by cell dysfunction and death in the brain, leading to progressive cognitive, psychiatric, and motor impairments. Despite molecular and cellular descriptions of the effects of the HD mutation, no effective pharmacological treatment is yet available. In addition to well-established alterations of glutamatergic and dopaminergic neurotransmitter systems, it is becoming clear that the GABAergic systems are also impaired in HD. GABA is the major inhibitory neurotransmitter in the brain, and GABAergic neurotransmission has been postulated to be modified in many neurological and psychiatric diseases. In addition, GABAergic neurotransmission is the target of many drugs that are in wide clinical use. Here, we summarize data demonstrating the occurrence of alterations of GABAergic markers in the brain of HD carriers as well as in rodent models of the disease. In particular, we pinpoint HD-related changes in the expression of GABA receptors (GABA Rs). On the basis that a novel GABA pharmacology of GABA Rs established with more selective drugs is emerging, we argue that clinical treatments acting specifically on GABAergic neurotransmission may be an appropriate strategy for improving symptoms linked to the HD mutation.

2‐(4‐methyl‐thiazol‐5‐yl) ethyl nitrate maleate‐potentiated GABAA receptor response in hippocampal neurons

“…Humans have 19 receptor subunits including α (1‐6), β (1‐3), and γ (1‐3). The most common complex that includes around 40% of the GABA A receptors is the α1β2γ2 combination . Barbiturates bind at a β‐subunit that is distinct from the benzodiazepine binding site .…”

Huntington’s Disease: A Review of the Known PET Imaging Biomarkers and Targeting Radiotracers

“…Alterations of GABA, or gamma-amino butyric acid, receptor expression has also been studied in the context of HD. GABAergic neurotransmission is severely impaired in HD -GABAergic striatal medium spiny projection neurons are particularly targeted during the course of the disease [48,49].…”

The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

“…This enhanced binding may in turn perturb the functionally important interaction between HAP1 and KIF5 motors, leading to a decrease in GABA A ‐receptor trafficking in neurons. The transport of GABA A receptors to synapses is critical to brain excitability, and a significant reduction in their abundance in synapses may contribute to the development of HD (Garret et al ).…”