Insights into GABA _A ergic system alteration in Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease that is characterized by a triad of motor, psychiatric and cognitive impairments. There is still no effective therapy to delay or halt the disease progress. The striatum and cortex are two particularly affected brain regions that exhibit dense reciprocal excitatory glutamate and inhibitory gamma-amino butyric acid (GABA) connections. Imbalance between excitatory and inhibitory signalling is known to greatly affect motor and cognitive processes. Emerging evidence supports the hypothesis that disrupted GABAergic circuits underlie HD pathogenesis. In the present review, we focused on the multiple defects recently found in the GABAergic inhibitory system, including altered GABA level and synthesis, abnormal subunit composition and distribution of GABAA receptors and aberrant GABAA receptor-mediated signalling. In particular, the important role of cation–chloride cotransporters (i.e. NKCC1 and KCC2) is discussed. Recent studies also suggest that neuroinflammation contributes significantly to the abnormal GABAergic inhibition in HD. Thus, GABAA receptors and cation–chloride cotransporters are potential therapeutic targets for HD. Given the limited availability of therapeutic treatments for HD, a better understanding of GABAergic dysfunction in HD could provide novel therapeutic opportunities.

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

“…To assess the potential impacts of mHTT in the cerebral tissue of parabionts, markers of various cell populations were assessed. In the cortex, NeuN [47], VGLUT1 [48,49] and GAD65-67 [50,51] were measured by western blot, as typical markers of cell populations targeted in HD. Consistent with disease features, an overall decrease was detected in NeuN (Fig.…”

Cortical and Striatal Circuits in Huntington’s Disease

“…Striatal inhibitory circuits also show multiple defects in HD animals. Electrophysiological recordings demonstrated a consistent increase in GABAergic transmission onto SPNs of different mouse models, which in some cases occurred already at the presymptomatic stage (Cepeda et al, 2004(Cepeda et al, , 2010(Cepeda et al, , 2013Centonze et al, 2005;Cummings et al, 2010;Indersmitten et al, 2015;Hsu et al, 2018). This increase in striatal inhibition, together with the loss of excitatory inputs, contributes to silencing of SPNs as disease progresses.…”

Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

“…Meanwhile, Huntington's disease is characterized pathologically by excessive dopaminergic activity and diminished gamma-aminobutyric acid (GABA) functions in the basal ganglia and clinically by abnormal movements, psychiatric disturbance, and cognitive deficits [21]. It is caused by a trinucleotide repeat expansion of the nucleotides cytosine, adenine, and guanine (a CAG expansion) in the Huntingtin (HTT) gene, located at the short arm of chromosome 4 [22].…”