This article does not aim to review in detail the properties of γ-aminobutyric acidA(GABAA)breceptors, because recent accounts of that topic are available. In this same journal, a review of the binding properties and pharmacology of these receptors has been published ([Sieghart, 1995][1]). Other

https://pharmrev.aspetjournals.org/content/pharmrev/50/2/291.full.pdf

International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.

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Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex

https://www.cogsci.ucsd.edu/~pineda/COGS260/amino%20acids/Tonically%20activie%20GABAa.pdf

Tonically active GABA A receptors: modulating gain and maintaining the tone.

GABA(A) receptors can mediate both 'phasic' synaptic inhibition and a persistent 'tonic' form of signaling. We show that, in the presence of intact GABA uptake, guinea pig hippocampal interneurons, but not pyramidal cells, express a tonic GABA(A) receptor-mediated conductance. This conductance was pharmacologically distinct from spontaneous inhibitory postsynaptic currents (IPSCs). Inhibiting GABA uptake resulted in the expression of a comparable GABA(A) receptor-mediated tonic conductance in pyramidal cells. Reducing the tonic conductance in interneurons enhanced their excitability and the inhibitory drive to pyramidal cells. These results point to a role for cell type-dependent tonic inhibition in regulating cortical excitability.

GABA uptake regulates cortical excitability via cell type–specific tonic inhibition

gamma-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter, activates a persistent low amplitude tonic current in several brain regions in addition to conventional synaptic currents. Here we demonstrate that GABA(A) receptors mediating the tonic current in hippocampal neurons exhibit functional and pharmacological properties different from those of quantal synaptic currents. Patch-clamp techniques were used to characterize miniature inhibitory postsynaptic currents (mIPSCs) and the tonic GABAergic current recorded in CA1 pyramidal neurons in rat hippocampal slices and in dissociated neurons grown in culture. The competitive GABA(A) receptor antagonists, bicuculline and picrotoxin, blocked both the mIPSCs and the tonic current. In contrast, mIPSCs but not the tonic current were inhibited by gabazine (SR-95531). Coapplication experiments and computer simulations revealed that gabazine bound to the receptors responsible for the tonic current but did not prevent channel activation. However, gabazine competitively inhibited bicuculline blockade. The unitary conductance of the GABA(A) receptors underlying the tonic current (approximately 6 pS) was less than the main conductance of channels activated during quantal synaptic transmission (approximately 15--30 pS). Furthermore, compounds that potentiate GABA(A) receptor function including the benzodiazepine, midazolam, and anesthetic, propofol, prolonged the duration of mIPSCs and increased tonic current amplitude in cultured neurons to different extents. Clinically-relevant concentrations of midazolam and propofol caused a greater increase in tonic current compared with mIPSCs, as measured by total charge transfer. In summary, the receptors underlying the tonic current are functionally and pharmacologically distinct from quantally activated synaptic receptors and these receptors represent a novel target for neurodepressive drugs.

Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons.

Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Here we show that the benzodiazepine diazepam can also increase the conductance of GABAA channels activated by low concentrations of GABA (0.5 or 5 microM) in rat cultured hippocampal neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAA channels tonically activated by low ambient concentrations of GABA in the extracellular environment may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.

Hippocampal GABA(A) channel conductance increased by diazepam

Chloride currents were activated by a low concentration of GABA (0.5 microM) in neonatal rat hippocampal neurons cultured for up to 14 days. Currents elicited by 0.5 microM GABA in neurons, voltage-clamped using the whole-cell technique with pipettes containing 149 mM Cl-, reversed close to 0 mV whether pipettes contained 144 mM Na+ or 140 mM Cs+, and were blocked by 100 microM bicuculline. Current-voltage curves showed outward rectification. Single channel currents appeared in cell-attached patches when the pipette tip was perfused with pipette solution containing 0.5 microM GABA and disappeared when a solution containing 100 microM bicuculline plus 0.5 microM GABA was injected into the pipette tip. The channels showed outward rectification and, in some patches, had a much lower probability of opening at hyperpolarized potentials. The average chord conductance in 10 patches hyperpolarized by 80 mV was 7.8 +/- 1.6 pS (SEM) compared with a chord conductance of 34.1 +/- 3.5 pS (SEM) in the same patches depolarized by 80 mV. Similar single channel currents were also activated in cell-free, inside-out patches in symmetrical chloride solutions when 0.5 microM GABA was injected into the pipette tip. The channels showed outward rectification similar to that seen in cell-attached patches, and some channels had a lower probability of opening at hyperpolarized potentials. The average chord conductance in 13 patches hyperpolarized by 80 mV was 11.8 +/- 2.3 pS (SEM) compared with 42.1 +/- 3.1 pS (SEM) in the same patches depolarized by 80 mV.

J P Curmi

Papers

Hippocampal GABA(A) channel conductance increased by diazepam

The influence of membrane potential on chloride channels activated by GABA in rat cultured hippocampal neurons.