Group III metabotropic glutamate receptors as autoreceptors in the cerebellar cortex

1 Group III metabotropic glutamate receptors (mGluRs) of the subtype 4a are localized within presynaptic active zones of cerebellar parallel fibre (PF)-Purkinje cell (PC) synapses. In order to investigate the conditions necessary for group III mGluR autoreceptor-activation by synaptically released glutamate, we characterized the effects of selective agonists and antagonists on excitatory postsynaptic currents (EPSCs) evoked by several distinct PF stimulation patterns. 2 The group III mGluR-selective agonist L-AP4 depressed evoked EPSCs at PF-PC synapses in rat brain slices with an EC50 of 2.4 mum and maximum inhibition of 80%. This L-AP4-induced depression was antagonized by the group III mGluR-selective antagonist MSOP with an estimated equilibrium dissaciation constant of 12.5 mum. 3 Paired-pulse or four-pulse PF stimulations did not activate presynaptic group III mGluRs as revealed by the lack of effect of I mm MSOP on relative test EPSC amplitudes with latencies of 250-500 ms. The potentiation of a test EPSC evoked 200-500 ms after a short tetanic burst (100 Hz for 60 ms), was also unchanged in the presence of MSOP. 4 Endogenous auto receptor-activation was revealed only during prolonged stimulation trains (10 Hz for 4.4 s), where, in the presence of 1 mm MSOP, the EPSC amplitudes were enhanced by 15%. 5 These observations support an autoreceptor function of group III mGluRs and a role in short-term synaptic plasticity at PF synapses. However, the low to moderate activation levels observed, despite the close spatial relation with glutamate release sites, suggests that additional mechanisms regulate receptor activation.