Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues

Crestani, Florence; Lorez, Matthias; Baer, Kristin; Essrich, Christian; Benke, Dietmar; Laurent, Jean Paul; Belzung, Catherine; Fritschy, Jean‐Marc; Lüscher, Bernhard; Möhler, Hanns

doi:10.1038/12207

Cited by 485 publications

(391 citation statements)

References 31 publications

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“…39,40 Interestingly, mice heterozygous for the GABA A -receptor g2 subunit display an almost inverse phenotype to that of dnActRIB mice, so that in g2 þ /À mice, enhanced behavioral inhibition toward natural aversive stimuli is associated with heightened diazepam responsiveness. 41 However, immunohistochemistry (Supplementary Figure 2) did not provide evidence for an altered expression pattern of the g2 subunit in hippocampi from dnActRIB mice. 42 The same was true for the d-subunit, 42 which targets GABA A receptors to extrasynaptic sites, where they produce a tonic inhibitory current (Supplementary Figure 2).…”

Section: Discussionmentioning

confidence: 93%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Discussionmentioning

confidence: 93%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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“…Generally speaking, knockout of these genes causes a lack of the coded subunits, induces compensatory GABA A subunit expressions and changes pharmacological actions of specific drugs; 27-38 knockouts of these genes are not vital to life, except the GABA A g2 subunit gene. 29 Among these studies, Reynolds et al 33 provides a direct evidence that the GABA A a1 subunit gene is involved in the nonlocomotor stereotyped activity (repetitive head bobbing, sniffing, vacuous chewing and rearing) during amphetamine sulfate administration. An observation worth mentioning here is that, while there was no difference of pentobarbital action between wild types and the b2À/À and a1À/À mice, the duration of loss of righting reflex produced by ethanol was decreased in male mice for both null types; no differences were observed in ethanol-induced sleep in female mice.…”

Section: Discussionmentioning

confidence: 99%

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

et al. 2003

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Family and twins studies have suggested that genetic factors are involved in the development of substance use disorders. Several unrelated case/control association studies have reported associations of the GABA A subunit genes on 5q33 with the development of alcohol dependence. We hypothesized that these particular GABA A subunit genes also contribute to the development of methamphetamine use disorder. To test our hypothesis, we recruited cases using a series of questionnaires. Among the polymorphic SNPs, significant differences between cases and controls were identified in the female sample in the rs2279020 of the GABA A a1 subunit gene, and the novel SNP rs4480617 in the GABA A g2 subunit gene. No associations were found in the male sample. Further haplotype analysis identified several marker blocks significantly associated with methamphetamine use disorder in females; each block consists of the rs4480617. Our study provides preliminary evidence that the GABA A subunit genes on 5q33 may preferentially contribute to methamphetamine use disorder in females. There is increasing evidence that substance use disorders are familial and that genetic factors explain a substantial degree of the familial aggregation. 3 Grove et al 4 studied a sample of 32 pairs of monozygotic twins reared apart, and reported that inherited factors explained 45% of the variance in drug abuse and dependence. Pickens et al 5 found that the variance attributable to genetic factors in abuse of illicit drugs is 31% in males and 22% in females. Similarly, Tsuang et al 6 reported that genetic factors account for 34% of the variance in the individual's risk of developing a drug use disorder; for stimulant abuse, 44% of the variance is attributable to genetic factors. The pairwise concordance rate for stimulant abuse was 14.1% for monozygotic twins and 5.3% for dizygotic twins. 7 The supporting evidence is also derived from animal studies. For example, knockout of the dopamine D4 receptor gene in mice result in animals that are supersensitive to several substances, including methamphetamine. 8 For the GABA A a1 knockout mice, administration of amphetamine sulfate caused an

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“…Additionally, GABA A receptors have been shown to be involved in modulating epilepsy, anxiety, learning and memory (DeLorey et al, 1998;Crestani et al, 1999;Mihalek et al, 1999).…”

Section: The Mouse Model and Molecular Mechanisms Of Fragile X Syndromementioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues

Cited by 485 publications

References 31 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

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