Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

Kuo, Yi-Hsuan; Chang, Ya-Gin; Chang, Ching-Pang; Siew, Jian Jing; Tsai, Chon‐Haw; Chern, Yijuang

doi:10.1002/mds.27107

Cited by 9 publications

(21 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent proteomic and bioinformatic data linked (m)Htt and KCC2 ( 25 , 26 ), and in the present study, we provide the biochemical validation of this protein interaction. We found that KCC2 interacts with both Htt and mHtt and KCC2 protein expression is decreased in the hippocampus of two predominant mouse models of HD (R6/2 and YAC128), consistent with a recent report of decreased KCC2 protein expression in the cortex and striatum of R6/2 mice ( 49 ). While a decrease in Slc12A5 mRNA accounts for some of the reduction in KCC2 protein expression, there is still KCC2 protein present in hippocampal neurons of HD mouse models, and thus additional mechanisms likely also regulate KCC2 protein expression.…”

Section: Discussionsupporting

confidence: 91%

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Dargaei

Bang

Mahadevan

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

134

View full text Add to dashboard Cite

SignificanceHuntington’s disease (HD) is a fatal neurodegenerative disorder that currently has no cure. Although HD is classically considered a motor disorder, HD patients experience learning and memory deficits years before the onset of motor symptoms, and these deficits resemble those observed in HD mouse models. In this work, using transgenic mouse models of HD, we demonstrate that the action of the neurotransmitter GABA has switched from inhibitory to excitatory. By treating HD mice with a clinically used diuretic (bumetanide), which restores inhibitory GABA, we rescued the learning and memory deficits. Our data suggest a potential therapeutic approach for the treatment of the cognitive deficits in early HD that can improve patient quality of life and reduce caregiver burden.

show abstract

Section: Discussionsupporting

confidence: 91%

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Dargaei

Bang

Mahadevan

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

134

View full text Add to dashboard Cite

show abstract

“…Decreased expression of KCC2 has been previously reported when increased NKCC1 was observed and may enable GABA to become excitatory . Likewise, our group and Dargaei et al reported reduced KCC2 expression in the cortices, striata, and hippocampi of multiple HD mouse models. Consistently, we and Dargaei et al reported that the stronger depolarization of E GABA was mainly because of the increased expression of NKCC1 in R6/2 mice rather than the reduced expression of KCC2, because acute application of an NKCC1 inhibitor, bumetanide, restored normal E GABA values.…”

Section: Discussionsupporting

confidence: 78%

“…RNA was isolated from mouse brains and human postmortem tissue and converted to cDNA using methods previously described . mRNA level was determined by quantitative PCR.…”

Section: Methodsmentioning

confidence: 99%

Enhanced Na⁺‐K⁺‐2Cl^‐ cotransporter 1 underlies motor dysfunction in huntington's disease

Kuo

Chang

Liu³

et al. 2019

Movement Disorders

Self Cite

View full text Add to dashboard Cite

Background Altered γ‐aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na‐K‐2Cl cotransporter‐1 is a key molecule that controls γ‐aminobutyric acid‐ergic signaling. However, the role of Na‐K‐2Cl cotransporter‐1 and efficacy of γ‐aminobutyric acid‐ergic transmission remain unknown in Huntington's disease. Methods We determined the levels of Na‐K‐2Cl cotransporter‐1 in brain tissue from Huntington's disease mice and patients by real‐time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin‐perforated patch‐clamp recordings were used to measure the Eγ‐aminobutyric acid in striatal brain slices. To inhibit Na‐K‐2Cl cotransporter‐1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno‐associated virus‐mediated delivery of Na‐K‐2Cl cotransporter‐1 short‐hairpin RNA into the striatum. Motor behavior assays were employed. Results Expression of Na‐K‐2Cl cotransporter‐1 was elevated in the striatum of R6/2 and Hdh150Q/7Q mouse models. An increase in Na‐K‐2Cl cotransporter‐1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of Eγ‐aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na‐K‐2Cl cotransporter‐1 in HD mice. Notably, pharmacological or genetic inhibition of Na‐K‐2Cl cotransporter‐1 rescued the motor deficits of R6/2 mice. Conclusions Our findings demonstrate that aberrant γ‐aminobutyric acid‐ergic signaling and enhanced Na‐K‐2Cl cotransporter‐1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society

show abstract

“…Besides the altered expression of GABA A Rs containing α1‐3 subunits essentially present in the postsynaptic domain, the expression of extrasynaptically localized α5‐ and δ‐containing GABA A Rs is also altered in human HD carriers and animal models . These extrasynaptic receptors are key factors in the control of local networks and are potential therapeutic targets for synthetic compounds or endogenous neuroactive steroids .…”

Section: Potential Therapeutic Avenuesmentioning

confidence: 99%

“…Besides the altered expression of GABA A Rs containing α1-3 subunits essentially present in the postsynaptic domain, the expression of extrasynaptically localized α5-and δ-containing GABA A Rs is also altered in human HD carriers and animal models. 69,94,95,129 These extrasynaptic receptors are key factors in the control of local networks 35 and are potential therapeutic targets for synthetic compounds or endogenous neuroactive steroids. 34,[130][131][132] On the basis of an increased expression of α5 in the striatum of R6/1 mice, 69 it would be relevant to test whether an α5-specific antagonist could slow disease progression or symptoms in HD, as is the case in mouse models of Down syndrome.…”

Section: P Otential Ther Apeuti C Aven Ue Smentioning

confidence: 99%

Alteration of GABAergic neurotransmission in Huntington's disease

Garret

Chazalon

et al. 2018

CNS Neurosci Ther

View full text Add to dashboard Cite

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.

show abstract

Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

Cited by 9 publications

References 64 publications

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Enhanced Na⁺‐K⁺‐2Cl^‐ cotransporter 1 underlies motor dysfunction in huntington's disease

Alteration of GABAergic neurotransmission in Huntington's disease

Contact Info

Product

Resources

About

Altered behavioral responses to gamma‐aminobutyric acid pharmacological agents in a mouse model of Huntington's disease

Cited by 9 publications

References 64 publications

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Enhanced Na+‐K+‐2Cl‐ cotransporter 1 underlies motor dysfunction in huntington's disease

Alteration of GABAergic neurotransmission in Huntington's disease

Contact Info

Product

Resources

About

Enhanced Na⁺‐K⁺‐2Cl^‐ cotransporter 1 underlies motor dysfunction in huntington's disease