We have previously described two distinct modes of GABA_A receptor activation in cerebellar granule cells (GCs) – the phasic activation of synaptic GABA_A receptors following vesicular GABA release and a tonic conductance arising from the persistent activation of extrasynaptic GABA_A receptors by low concentrations of ambient GABA (Brickley et al. 1996). Recent studies have suggested that in the mature rat cerebellum spontaneous GABA_A receptor-mediated synaptic currents (sIPSCs) are rare and the GABA giving rise to the tonic conductance is not produced by conventional vesicular release from Golgi cell interneurons (Wall & Usowicz, 1997; Hamann et al. 2002). These observations have called into question the function of both phasic and tonic inhibition in the dynamic control of granule cell excitability (De Schutter, 2002).

We made whole-cell recordings from GCs in slices prepared from 7- to 200-day-old mice (P7-P200) in accordance with the UK Animals (Scientific Procedures) Act, 1986, as described previously. Across all ages, over 80 % of GCs exhibited sIPSCs (186 out of 221 GCs in 64 animals). Even at P200 sIPSCs were readily detected, occurring at a frequency of 0.8 ± 0.3 Hz (mean ± S.E.M.) in six out of seven GCs, similar to the situation previously reported in P35 animals (Brickley et al. 2001). In mature animals, addition of TTX (1 µM) or removal of external Ca²⁺ resulted in a significant reduction in the frequency of IPSCs (average age P66 ± 14, n = 22). The miniature IPSCs that remained in the presence of TTX occurred at a frequency of 0.09 ± 0.02 Hz. This reduction in vesicular GABA release following TTX application or Ca²⁺ removal also resulted in a 56 ± 7 % (n = 15) reduction in the tonic GABA_A receptor-mediated conductance in mature GCs. This result contrasts with previous reports that the tonic conductance was TTX insensitive (Wall & Usowicz, 1997; Hamann et al. 2002).

In conclusion, action potential-dependent release of GABA from cerebellar Golgi cells occurred at all ages. Reduction in vesicular GABA release affected not only the frequency of phasic IPSCs but also the magnitude of the tonic GABA_A receptor-mediated conductance. Therefore, the overall level of Golgi cell activity will modulate both phasic and tonic inhibition in mature GCs, an observation which is consistent with current theories of cerebellar function (De Schutter, 2002).

This work was supported by The Wellcome Trust.