Cerebellar granule‐cell‐specific GABA<sub>A</sub> receptors attenuate benzodiazepine‐induced ataxia: evidence from α6‐subunit‐deficient mice

Korpi, Esa R.; Koikkalainen, P.; Vekovischeva, Olga Y.; Mäkelä, Riikka; Kleinz, Raymonde; Uusi‐Oukari, Mikko; Wisden, William

doi:10.1046/j.1460-9568.1999.00421.x

Cited by 82 publications

(48 citation statements)

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“…High doses of ethanol (2 g kg −1 ) have been reported to similarly impair wild-type and Gabra6 −/− mice in rotarod tests 40 , and at ethanol doses of 3.5 g kg −1 , no significant differences have been observed between wild type and Gabra6 −/− in a LORR test 41,42 . At such high ethanol doses, we also find no change for Gabra6 100R/100R and Gabra6 100Q/100Q rats in rotarod performance (data not shown) or in LORR (Fig 5e,f).…”

Section: Gabra6 100q Allele and Behavioral Sensitivity To Ethanolmentioning

confidence: 94%

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

et al. 2005

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Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABA A receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6 100R/100R and Gabra6 100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.Humans have been consuming alcohol for thousands of years, and the use of alcoholic beverages pervades human culture and society and can have substantial health effects 1 . Different mechanisms by which ethanol might depress brain function have been proposed based on ethanol's ability to modulate a wide variety of ion channels 2-4 , neurotransmitter receptors 5-10 and transporters 11 . Among these diverse targets, however, GABARs are arguably the most attractive candidates. This is in part because other classes of known GABAR modulators such as benzodiazepines, barbiturates and certain anesthetics lead to behavioral effects that closely resemble ethanol intoxication. Yet despite strong evidence implicating GABARs in ethanol's action, critical details remain unclear. For instance, although it is known that native GABARs are heteropentamers assembled from 19 possible subunits 12,13 , it has not been possible to link the activity of particular GABAR subunits to changes in behavioral sensitivity to ethanol.Recent studies suggest that specific combinations of GABAR subunits (those containing α4β3δ and α6β3δ) are uniquely sensitive to ethanol, showing dose dependencies that mirror blood alcohol levels associated with intoxication in humans 9,10 . GABARs containing α4 and δ subunits are expressed in many brain regions 14,15 , but α6 is found in only two types of neurons (cerebellar granule cells and granule cells in the cochlear nucleus) and is expressed together with δ only in cerebellar granule cells 14,16,17 . In granule cells α6 and δ combine with β subunits Correspondence should be addressed to M.W. (mwallner@mednet.ucla.edu) or T.S.O. (otist@ucla.edu). 3 These authors contributed equally to this work. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We set out to examine whether such extrasynaptic GABARs containing α6 and δ subunits account for behavioral effects of ethanol at moderately intoxicating doses. To link these particular GABARs to behavioral sensitivity, we first characterized a naturally occurring single-nucleotide polymo...

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Section: Gabra6 100q Allele and Behavioral Sensitivity To Ethanolmentioning

confidence: 94%

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

et al. 2005

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“…No compensation by the a1 subunit was detected in glomeruli or in the molecular layer of a6 0/0 mice (73), indicating that the a1 and a6 subunit are regulated independently, although their genes are present in the same chromosomal cluster (75). Interestingly, while a6 0/0 mice display no major spontaneous phenotype, a clear motor deficit could be shown upon treatment with diazepam, which could be reversed by flumazenil, indicating that it was mediated by the remaining, mainly postsynaptic, GABA A receptors in these mice (76).…”

Section: Effects Of Targeted Subunit Gene Deletion On Cerebellar Gabamentioning

confidence: 99%

“…Functionally, a loss of modulation of sIPSCs by the neurosteroid THDOC selectively occurs in granule cells, but not stellate cells of d 0/0 mice (78), underscoring the importance of d-GABA A receptors for the in vivo action of neurosteroids (79). Behaviorally, deletion of the d subunit gene produces no overt impairment in motor function or motor learning, similarly to the a6 subunit gene (76). This observation should not lead to the conclusion that tonic inhibition mediated by extrasynaptic GABA A receptors in granule cells is irrelevant.…”

Section: Effects Of Targeted Subunit Gene Deletion On Cerebellar Gabamentioning

confidence: 99%

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

Fritschy

Panzanelli

2006

Cerebellum

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GABA A receptors form heteromeric GABA-gated chloride channels assembled from a large family of subunit genes. In cerebellum, distinct GABA A receptor subtypes, differing in subunit composition, are segregated between cell types and synaptic circuits. The cerebellum therefore represents a useful system to investigate the significance of GABA A receptor heterogeneity. For instance, studies of mice carrying targeted deletion of major GABA A receptor subunit genes revealed the role of a subunit variants for receptor assembly, synaptic targeting, and functional properties. In addition, these studies unraveled mandatory association between certain subunits and demonstrated distinct pharmacology of receptors mediating phasic and tonic inhibition. Although some of these mutants have a profound loss of GABA A receptors, they exhibit only minor impairment of motor function, suggesting activation of compensatory mechanisms to preserve inhibitory networks in the cerebellum. These adaptations include an altered balance between phasic and tonic inhibition, activation of voltageindependent K + conductances, and upregulation of GABA A receptors in interneurons that are not affected directly by the mutation. Deletion of the a1 subunit gene leads to complete loss of GABA A receptors in Purkinje cells. A striking alteration occurs in these mice, whereby presynaptic GABAergic terminals are preserved in the molecular layer but make heterologous synapses with spines, characterized by a glutamatergic-like postsynaptic density. During development of a1 0/0 mice, GABAergic synapses are initially formed but are replaced upon spine maturation. These findings suggest that functional GABA A receptors are required for long-term maintenance of GABAergic synapses in Purkinje cells.

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“…One of the most commonly used tests of motor incoordination is the rotarod (1)(2)(3)(4), which has two variants: the accelerating rotarod (ARR) and the fixed-speed rotarod (FSRR). Studies of inbred strains (5)(6)(7)(8), selected lines (9), and transgenic animals (10)(11)(12) have shown that rotarod performance is highly influenced by genetic background in mice. Genetically distinct mice often differ in their undrugged ability to perform, and differ in their sensitivities to ethanol and other drugs on the task.…”

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confidence: 99%

Assessment of genetic susceptibility to ethanol intoxication in mice

Rustay

Wahłsten

Crabbe

2003

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

102

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Increased use of gene manipulation in mice (e.g., targeted or random mutagenesis) has been accompanied by increased reliance on a very few rapid and simple behavioral assays, each of which aspires to model a human behavioral domain. Yet, each assay comprises multiple traits, influenced by multiple genetic factors. Motor incoordination (ataxia), a common characteristic of many neurological disorders, may reflect disordered balance, muscle strength, proprioception, and͞or patterned gait. Impaired motor performance can confound interpretation of behavioral assays of learning and memory, exploration, motivation, and sensory competence. The rotarod is one of the most commonly used tests to measure coordination in mice. We show here that exactly how the rotarod test is performed can markedly alter the apparent patterns of genetic influence both in undrugged performance and sensitivity to ethanol intoxication. However, when tested with well chosen parameters, the accelerating rotarod test showed very high inter-and intralaboratory reliability. Depending on test conditions, ethanol can either disrupt or enhance performance in some strains. Genetic contribution to performance on the accelerating versus the fixed-speed rotarod assay can be completely dissociated under some test conditions, and multiple test parameters are needed to assess the range of genetic influence adequately.T he loss of motor coordination (ataxia) is a common characteristic of many neurological disorders and a frequent endpoint for studies of drug intoxication. Therefore, behavioral assays that model ataxia are of great importance to researchers who are interested in learning more about the mechanisms of drug action and disease. One of the most commonly used tests of motor incoordination is the rotarod (1-4), which has two variants: the accelerating rotarod (ARR) and the fixed-speed rotarod (FSRR). Studies of inbred strains (5-8), selected lines (9), and transgenic animals (10-12) have shown that rotarod performance is highly influenced by genetic background in mice. Genetically distinct mice often differ in their undrugged ability to perform, and differ in their sensitivities to ethanol and other drugs on the task.Although the rotarod is widely used in biomedical research, there is little consensus on the ideal parameters and test schedules to produce optimal results. We have recently completed studies in genetically heterogeneous mice examining the influence of different rod diameters, rotation rate, and training regimens on rotarod performance, as well as their effects on sensitivity to ethanol intoxication. We obtained some expected results (e.g., training on the ARR improved performance, and performance was influenced by acceleration rate). More surprisingly, we found that higher acceleration rates suppressed sensitivity to ethanol intoxication. We also found that rod diameter did not markedly affect performance, provided that the diameter was large enough to prevent passive rotation on the rod (13).Many researchers appear to design behavioral ...

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Cerebellar granule‐cell‐specific GABA_A receptors attenuate benzodiazepine‐induced ataxia: evidence from α6‐subunit‐deficient mice

Cited by 82 publications

References 56 publications

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

Assessment of genetic susceptibility to ethanol intoxication in mice

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Cerebellar granule‐cell‐specific GABAA receptors attenuate benzodiazepine‐induced ataxia: evidence from α6‐subunit‐deficient mice

Cited by 82 publications

References 56 publications

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

Assessment of genetic susceptibility to ethanol intoxication in mice

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Cerebellar granule‐cell‐specific GABA_A receptors attenuate benzodiazepine‐induced ataxia: evidence from α6‐subunit‐deficient mice