Neuronal plasticity is achieved by regulation of the expression of genes for neurotransmitter receptors such as the type A receptor (GABAAR) for g-aminobutyric acid. The subunit composition of native GABAA receptors plays a crucial role in defining their function in the physio- logical and pharmacological modulation of neuronal excitability and associated behaviour. The pattern of GABAAR gene expression is affected by environmental stimuli, physiological processes, and drugs that modulate GABAAR-mediated neurotransmission. However, whether such induced changes in gene expression for a given GABAAR subunit are identical among different neuronal populations that express that subunit in a specific brain area is not known. We now show that prolonged exposure to ethanol had no effect on expression of the d subunit of GABAARs at the mRNA or protein level in cere- bellar granule neurons, it increased the abundance of d subunit mRNA and protein in hippocampal neurons. Subsequent ethanol withdrawal transiently down-regulated d subunit expression in cerebellar granule neurons and gradually normalized that in hippocampal neurons. On the contrary the expression of other GABAARs subunits (a4 and g2) follow the same patter of changes in the two neuronal cell types in culture. These effects of ethanol exposure and withdrawal were accom- panied by corresponding functional changes in GABAARs. These find- ings reveal complex and distinct mechanisms of regulation of the expression of GABAARs in different neuronal types.
Molecular mechanisms of tolerance to and withdrawal of GABA(A) receptor modulators
FOLLESA, PAOLO;BIGGIO, FRANCESCA;Gorini G;
2005-01-01
Abstract
Neuronal plasticity is achieved by regulation of the expression of genes for neurotransmitter receptors such as the type A receptor (GABAAR) for g-aminobutyric acid. The subunit composition of native GABAA receptors plays a crucial role in defining their function in the physio- logical and pharmacological modulation of neuronal excitability and associated behaviour. The pattern of GABAAR gene expression is affected by environmental stimuli, physiological processes, and drugs that modulate GABAAR-mediated neurotransmission. However, whether such induced changes in gene expression for a given GABAAR subunit are identical among different neuronal populations that express that subunit in a specific brain area is not known. We now show that prolonged exposure to ethanol had no effect on expression of the d subunit of GABAARs at the mRNA or protein level in cere- bellar granule neurons, it increased the abundance of d subunit mRNA and protein in hippocampal neurons. Subsequent ethanol withdrawal transiently down-regulated d subunit expression in cerebellar granule neurons and gradually normalized that in hippocampal neurons. On the contrary the expression of other GABAARs subunits (a4 and g2) follow the same patter of changes in the two neuronal cell types in culture. These effects of ethanol exposure and withdrawal were accom- panied by corresponding functional changes in GABAARs. These find- ings reveal complex and distinct mechanisms of regulation of the expression of GABAARs in different neuronal types.
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