Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why?

Abstract

Although GABA(A) receptors are widely distributed at inhibitory synapses on dendrites and cell bodies of neurons, they also occur in other places, in particular at synapses made on axons and in extrasynaptic membranes. This review summarises some of the evidence that presynaptic receptors modulate transmission not only at primary afferents in the spinal cord, but also at a variety of sites in the brain, including hippocampal mossy fibres. These receptors modulate transmitter release via several different mechanisms. Another form of unconventional GABA(A) receptor-mediated signalling is the mediation of a tonic conductance, seen in granule cells of the cerebellum and dentate gyrus and also in hippocampal interneurons. Tonic signalling appears to be mediated by extrasynaptic receptors. The adaptive significance of this form of signalling remains poorly understood.

Fig. 1

Evidence for GABA_A receptors modulating mossy fibre excitability. Top: granule cells were recorded in cell-attached mode in acute rodent hippocampal slices, and a threshold-straddling stimulus was applied via an electrode positioned in stratum lucidum. This resulted in intermittent antidromic action potentials, recorded as action currents (AC). Local pressure application of the GABA_A agonist muscimol close to the stimulation site decreased the axon excitability (summary plot showing mean AC success rate and SEM for four cells). Bottom: following ‘break-in’ with a pipette containing a high [Cl⁻], designed to depolarise the GABA_A reversal potential, the same application of muscimol caused an increase in axon excitability (30 min were allowed to elapse following break-in to allow Cl⁻ to equilibrate). The individual sweeps on the right were obtained from one example cell, showing intermittent failures to evoke an AC. Reproduced from Ruiz et al. (2003).

Fig. 2

Pharmacological separation of tonic and phasic GABA_A receptor-mediated signalling in hippocampal neurons. (a) An interneuron (IN, top) and a pyramidal cell (PC) were recorded in the CA1 region of acute guinea pig brain slices with a high [Cl⁻] pipette solution, in the presence of glutamate receptor antagonists (holding voltage −70 mV). The holding current shows intermittent inward transients, reflecting spontaneous inhibitory postsynaptic currents. Picrotoxin perfusion to block GABA_A receptors abolished the synaptic currents, but also produced an outward shift in holding current in the interneuron but not in the pyramidal cell, reflecting the removal of a tonic GABA_A conductance. (b) A low concentration of the GABA_A receptor antagonist gabazine (SR95531, SR) abolished spontaneous synaptic currents, but had no effect on the tonic current. Tonic and phasic GABA_A receptor-mediated currents thus have distinct pharmacological profiles. Reproduced from Semyanov et al. (2003).