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Pharmacology, physiology and regulation of tonic GABAA conductances

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GABAA receptors mediate two forms of signaling in the brain: phasic and tonic. Phasic signaling (e.g., IPSCs) is mediated by synaptic GABAA receptors, while tonic signaling (e.g., tonic conductances) is mediated by extrasynaptic GABAA receptors. Tonic GABAA conductances, discovered over 20 years ago, are ...

GABAA receptors mediate two forms of signaling in the brain: phasic and tonic. Phasic signaling (e.g., IPSCs) is mediated by synaptic GABAA receptors, while tonic signaling (e.g., tonic conductances) is mediated by extrasynaptic GABAA receptors. Tonic GABAA conductances, discovered over 20 years ago, are found in many brain regions. These conductances reflect local ambient concentrations of GABA and are expressed in a cell-type specific manner. This specificity is determined by a number of factors, including the expression and pharmacologic properties of extrasynaptic GABAA receptors and the levels of local GABA release and uptake. Indeed, tonic GABAA conductances are mediated by specific sets of heterogeneous receptors in different cell types. These receptors have a higher affinity to GABA and slower inactivation and desensitization kinetics than synaptic GABAA receptors. Moreover, extrasynaptic GABAA receptors have different pharmacologic properties, which determine their high sensitivity to endogenous factors such as neurosteroids, or exogenous factors such as alcohol. The pharmacologic properties also make extrasynaptic GABAA receptors an attractive target for drug development. In addition to agonist-mediated tonic GABAA conductance, the conductance can originate from spontaneous GABAA receptor openings. Agonist-independent tonic conductance represents a ‘floor’ level of this conductance, which is regulated by receptor expression. Further agonist-dependent increases in tonic GABAA conductance are mediated by GABA spillover or extrasynaptic GABA release, for example by astrocytes. These sources are activity-regulated, suggesting that the level of tonic GABAA conductance is not stationary in the brain. In addition, the magnitude of tonic GABAA conductance is tightly linked to GABA metabolism. For instance, genetic deletion of glutamic acid decarboxylase 65K has a relatively minor effect on synaptic GABAA-mediated signaling, while significantly reducing tonic GABAA conductance.
Tonic GABAA conductances produce different physiologic effects depending on the type of neuron. For example, they change neuronal gain in cerebellar granular cells, but offset input-output characteristics in hippocampal pyramidal cells. Tonic GABAA conductances are commonly called tonic inhibition, which in many cases is true. In adult hippocampal interneurons, however, baseline tonic GABAA conductances are excitatory because the small depolarization produced by GABA in these cells triggers other voltage-dependent conductances. These effects of tonic GABAA conductance can affect the local network operation, and thus are important for brain function. Tonic GABAA conductances are involved in regulating excitation flow in the hippocampus, regulating the generation of brain rhythms, play an important role in ovarian cycle-related mood changes in women, and are involved in neurodegenerative disorders such as epilepsy and schizophrenia. Moreover, these disorders can trigger plasticity of tonic GABAA conductances, which has to be taken into account for drug development.


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