Whether presynaptic ionotropic GABA receptors can modulate neurotransmitter release in the cerebral cortex is not known. We have recently shown that GABA_A receptor activation modulates the excitability of rodent hippocampal mossy fibres in response to extracellular stimulation (Ruiz, Fabian-Fine, Scott, Rusakov and Kullmann, submitted). We also found that blocking GABA_A receptors alters the threshold for antidromic recruitment of mossy fibres, implying that they are tonically active. In order to determine whether presynaptic GABA_A receptors can modulate orthodromic signalling, we performed fast multi-photon imaging of action potential-dependent Ca²⁺ transients in individual mossy fibre varicosities.

Hippocampal slices were obtained from guinea-pigs killed by cervical dislocation. Granule cells were held in whole cell voltage clamp, with pipettes filled with a low [Cl^–] solution containing the Ca²⁺-sensitive dye Fluo-4 (in some experiments the morphological tracer Alexa 594 was also added). Antidromic action potentials were delivered via an extracellular stimulating electrode positioned in stratum lucidum. These evoked a rapid Ca²⁺ transient in hilar varicosities, which exhibited a biphasic dependence on somatic holding potential that peaked at approximately -85 mV. This biphasic dependence on membrane potential is qualitatively consistent with the effects of K⁺ and kainate on orthodromic transmission reported by Schmitz et al. (2001). The amplitude of the Ca²⁺ transient when the cell was held at -70 mV was attenuated by blocking GABA_A receptors with 10 µM SR95531 (reduction to 66 ± 4 % of baseline; P < 0.001, t test, n = 9).

These results imply that axonal GABA_A receptors play a potentially important role in modulating information flow to the hippocampus.