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 EC(50) of 2.4 microM 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 microM. 3. Paired-pulse or four-pulse PF stimulations did not activate presynaptic group III mGluRs as revealed by the lack of effect of 1 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 autoreceptor-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.
Lorez
Matthias
M
Pharma Division Pre-clinical Research, F Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland. matthias.lorenz@roche.com
Humbel
Urs
U
Pflimlin
Marie-Claire
MC
Kew
James N C
JN
D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D002525:Cerebellar Cortex / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA; D017470:Receptors, Glutamate / Q000502:physiology*
C114785:2-amino-4-phosphono-propinate; D017660:Autoreceptors; D011422:Propionates; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C104723:glutamate receptor ionotropic, AMPA 3