Neuronal activity and its influence on developmentally regulated GABAA receptor expression in cultured mouse cerebellar granule cells

Ives, Jane H.; Drewery, Debra L.; Thompson, Christopher L.

doi:10.1016/s0028-3908(02)00164-8

Cited by 16 publications

(24 citation statements)

References 38 publications

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“…Measurements from conditional Fmr1 knockout animals show that FMRP expression may be affecting the level of synaptic GABA and the number of GABA A Rs independent of whether or not it is absent either in inhibitory neurons or in excitatory principal neurons. This is perhaps not surprising given the dependence of GABA A R expression on neuronal activity (Ives et al, 2002;Kilman et al, 2002). However, the observation that the restoration of FMRP in inhibitory neurons in conditional rescue mice does not rescue GABA A R maturation defects interestingly suggests that FMRP function in inhibitory neurons is not critical for postsynaptic receptor maturation.…”

Section: Discussionmentioning

confidence: 96%

Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

et al. 2013

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Fragile X Syndrome (FXS) is a debilitating neurodevelopmental disorder thought to arise from disrupted synaptic communication in several key brain regions including the amygdala - a central processing center for information with emotional and social relevance. Recent studies reveal defects in both excitatory and inhibitory neurotransmission in mature amygdala circuits in Fmr1-/y mutants, the animal model of FXS. However, whether these defects are the result of altered synaptic development or simply faulty mature circuits remains unknown. Using a combination of electrophysiological and genetic approaches, we show the development of both pre- and postsynaptic components of inhibitory neurotransmission in the FXS amygdala is dynamically altered during critical stages of neural circuit formation. Surprisingly, we observe that there is a homeostatic correction of defective inhibition, which, despite transiently restoring inhibitory synaptic efficacy to levels at or beyond those of control, ultimately fails to be maintained. Using inhibitory interneuron-specific conditional knockout and rescue mice, we further reveal that Fragile X Mental Retardation Protein (FMRP) function in amygdala inhibitory microcircuits can be segregated into distinct pre- and postsynaptic components. Collectively, these studies reveal a previously unrecognized complexity of disrupted neuronal development in FXS and therefore have direct implications for establishing novel temporal and region-specific targeted therapies to ameliorate core amygdala-based behavioral symptoms.

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Section: Discussionmentioning

confidence: 96%

Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

et al. 2013

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“…For example, culturing rat cerebellar granule neurons at 25 mmol/l K ϩ reduced ␤3, as well as ␣1, ␣6, and ␤2 subunit mRNA levels (41). The importance of Ca 2ϩ entry-dependent pathways in the control of gene expression is well documented.…”

Section: Discussionmentioning

confidence: 99%

Glucose-Dependent Regulation of γ-Aminobutyric Acid (GABAA) Receptor Expression in Mouse Pancreatic Islet α-Cells

2007

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The mechanism(s) by which glucose regulates glucagon secretion both acutely and in the longer term remain unclear. Added to isolated mouse islets in the presence of 0.5 mmol/l glucose, ␥-aminobutyric acid (GABA) inhibited glucagon release to a similar extent (46%) as 10 mmol/l glucose (55%), and the selective GABA A receptor (GABA A R) antagonist SR95531 substantially reversed the inhibition of glucagon release by high glucose. GABA A R ␣4, ␤3, and ␥2 subunit mRNAs were detected in mouse islets and clonal ␣TC1-9 cells, and immunocytochemistry confirmed the presence of GABA A Rs at the plasma membrane of primary ␣-cells. Glucose dose-dependently increased GABA A R expression in both islets and ␣TC1-9 cells such that mRNA levels at 16 mmol/l glucose were ϳ3.0-fold (␣4), 2.0-fold (␤3), or 1.5-fold (␥2) higher than at basal glucose concentrations (2.5 or 1.0 mmol/l, respectively). These effects were mimicked by depolarizing concentrations of K ؉ and reversed by the L-type Ca 2؉ channel blocker nimodipine. We conclude that 1) release of GABA from neighboring ␤-cells contributes substantially to the acute inhibition of glucagon secretion from mouse islets by glucose and 2) that changes in GABA A R expression, mediated by changes in intracellular free Ca 2؉ concentration, may modulate this response in the long term. Diabetes 56: 320 -327, 2007

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“…The mechanism underlying the reduced expression of GABA A R subunit mRNAs in SW mice likely involves a transcriptional problem. GABA A R subunit gene expression is known to be sensitive to regulation by depolarization, cAMP, brain derived neurotrophic factor, and mitogen-activated protein kinases (MAPK) (Bulleit and Hsieh, 2000;Thompson et al, 2000;Ives et al, 2002;Obrietan et al, 2002). The 5-HT 1A R couples to multiple G␣ i/o -protein-signaling pathways including the inhibition of adenylyl cyclase, activation of nuclear factor-B, and the MAPK/ ERK (extracellular signal-regulated kinase) pathway (Raymond et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Variability in the Benzodiazepine Response of Serotonin 5-HT_1AReceptor Null Mice Displaying Anxiety-Like Phenotype: Evidence for Genetic Modifiers in the 5-HT-Mediated Regulation of GABA_AReceptors

Bailey¹,

Tóth²

2004

J. Neurosci.

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Benzodiazepines (BZs) acting as modulators of GABA A receptors (GABA A Rs) are an important group of drugs for the treatment of anxiety disorders. However, a large inter-individual variation in BZ sensitivity occurs in the human population with some anxiety disorder patients exhibiting diminished sensitivity to BZ and reduced density of GABA A Rs. The mechanism underlying BZ treatment resistance is not known, and it is not possible to predict whether an anxiety patient will respond to BZ. 5-Hydroxytryptamine 1A receptor (5-HT 1A R) null mice (R Ϫ/Ϫ ) on the Swiss-Webster (SW) background reproduce several features of BZ-resistant anxiety; they exhibit anxiety-related behaviors, do not respond to BZ, have reduced BZ binding, and have decreased expression of the major GABA A R subunits ␣1 and ␣2. Here, we show that R Ϫ/Ϫ mice on the C57Bl6 (B6) background also have anxiety phenotype, but they respond to BZ and have normal GABA A R subunit expression. This indicates that the 5-HT 1A R-mediated regulation of GABA A R ␣ subunit expression is subject to genetic modification. Hybrid SW/B6-R Ϫ/Ϫ mice also exhibit BZ-resistant anxiety, suggesting that SW mice carry a genetic modifier, which mediates the effect of the 5-HT 1A R on the expression of GABA A R ␣ subunits. In addition, we show that this genetic interaction in SW mice operates early in postnatal life to influence the expression of GABA A R ␣ subunits at the transcriptional level. These data indicate that BZ-resistant anxiety results from a developmental arrest of GABA A R expression in SW-R Ϫ/Ϫ mice, and a similar mechanism may be responsible for the BZ insensitivity of some anxiety patients.

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Neuronal activity and its influence on developmentally regulated GABAA receptor expression in cultured mouse cerebellar granule cells

Cited by 16 publications

References 38 publications

Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

Glucose-Dependent Regulation of γ-Aminobutyric Acid (GABAA) Receptor Expression in Mouse Pancreatic Islet α-Cells

Variability in the Benzodiazepine Response of Serotonin 5-HT_1AReceptor Null Mice Displaying Anxiety-Like Phenotype: Evidence for Genetic Modifiers in the 5-HT-Mediated Regulation of GABA_AReceptors

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Neuronal activity and its influence on developmentally regulated GABAA receptor expression in cultured mouse cerebellar granule cells

Cited by 16 publications

References 38 publications

Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

Glucose-Dependent Regulation of γ-Aminobutyric Acid (GABAA) Receptor Expression in Mouse Pancreatic Islet α-Cells

Variability in the Benzodiazepine Response of Serotonin 5-HT1AReceptor Null Mice Displaying Anxiety-Like Phenotype: Evidence for Genetic Modifiers in the 5-HT-Mediated Regulation of GABAAReceptors

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Variability in the Benzodiazepine Response of Serotonin 5-HT_1AReceptor Null Mice Displaying Anxiety-Like Phenotype: Evidence for Genetic Modifiers in the 5-HT-Mediated Regulation of GABA_AReceptors