Session Time: 12:00pm-1:30pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To investigate (1) the expression of GABAA receptors and KCC2 in both Huntington’s disease (HD) mouse models and patients and (2) the inhibitory effect of drugs that act via synaptic and extra-synaptic GABAA receptors on a HD mouse model.
Background: Altered balance of glutamatergic and GABAergic neurotransmission in the cortical-striatal circuit has been proposed as a potential pathophysiological process in HD. Although the cortico-striatal excitotoxicity is well documented in HD, the pathological regulation of inhibitory neurotransmission is less known. GABA exerts its action of phasic and tonic inhibition respectively via synaptic and extrasynaptic GABAA receptors. The polarity of GABAAR signaling depends on the precise regulation of KCC2 and NKCC1.
Methods: Two transgenic mouse models of HD, R6/2 and N171-82Q, were used in this study. The post-mortem human caudate were obtained from the Human Brain and Spinal Fluid Resource Center, Los Angeles. Real-time quantitative polymerase chain reaction, western blot and immunochemical staining techniques were used to measure gene and protein expression. The effect of diazepam and gaboxadol on spontaneous locomotor activity was measured in R6/2 mice.
Results: We reported changes in the gene expression of GABAAR α1 and δ subunits in the cortex and striatum of two transgenic mouse model of HD. The protein expression of KCC2 was decreased in HD mice, which may alter the nature of GABAAR signaling. Besides, KCC2 activity was showed to be activated by its interacting protein- brain-type creatine kinase (CKB), an enzyme in the production of ATP, which is decreased in HD mouse models and patients. Our finding suggested that decreased physical coupling between CKB and KCC2 in R6/2 mice. We also found that the post-morten caudate of HD patients showed a trend of lower GABAAR α2, δ subunits and KCC2 transcripts than those from age-matched controls. Moreover, compared with WT mice, R6/2 mice exhibited a lower diazepam- induced motor impairment and gaboxadol-induced sedation.
Conclusions: Our findings provided evidences of altered expression of GABAAR subunits and KCC2 in HD brain, which could contribute to the abnormally GABAergic signaling and responses of GABAAR drugs. Our study also raised the concern of attenuated inhibitory effect of these clinically used GABAAR drugs on HD patients.
EMBO Conference, Neural development, 4 – 8 December 2015, Taipei, Taiwan.
To cite this abstract in AMA style:Y.T. Hsu, Y.G. Chang, H.M. Chen, Y. Chern. Dysregulations of GABAergic neurotransmission in Huntington’s disease brain [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/dysregulations-of-gabaergic-neurotransmission-in-huntingtons-disease-brain/. Accessed February 21, 2024.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/dysregulations-of-gabaergic-neurotransmission-in-huntingtons-disease-brain/