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1 Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, University Road, Leicester LE1 9HN, UK
2 Department of Computing Science and Mathematics, University of Stirling, Stirling FK9 4LA, Scotland, UK
3 MRC Toxicology Unit, University of Leicester, PO Box 138, University Road, Leicester LE1 9HN, UK
Presynaptic group III metabotropic glutamate receptor (mGluR) activation by exogenous agonists (such as L-2-amino-4-phosphonobutyrate (L-AP4)) potently inhibit transmitter release, but their autoreceptor function has been questioned because endogenous activation during high-frequency stimulation appears to have little impact on synaptic amplitude. We resolve this ambiguity by studying endogenous activation of mGluRs during trains of high-frequency synaptic stimuli at the calyx of Held. In vitro whole-cell patch recordings were made from medial nucleus of the trapezoid body (MNTB) neurones during 1 s excitatory postsynaptic current (EPSC) trains delivered at 200 Hz and at 37°C. The group III mGluR antagonist (R,S)-cyclopropyl-4-phosphonophenylglycine (CPPG, 300 µM) had no effect on EPSC short-term depression, but accelerated subsequent recovery time course (
: 4.6 ± 0.8 s to 2.4 ± 0.4 s, P
= 0.02), and decreased paired pulse ratio from 1.18 ± 0.06 to 0.97 ± 0.03 (P
= 0.01), indicating that mGluR activation reduced release probability (P). Modelling autoreceptor activation during repetitive stimulation revealed that as P declines, the readily releasable pool size (N) increases so that the net EPSC (NP) is unchanged and short-term depression proceeds with the same overall time course as in the absence of autoreceptor activation. Thus, autoreceptor action on the synaptic response is masked but the synapse is now in a different state (lower P, higher N). While vesicle replenishment clearly underlies much of the recovery from short-term depression, our results show that the recovery time course of P also contributes to the reduced response amplitude for 1–2 s. The results show that passive equilibration between N and P masks autoreceptor modulation of the EPSC and suggests that mGluR autoreceptors function to change the synaptic state and distribute metabolic demand, rather than to depress synaptic amplitude.
(Received 16 March 2005;
accepted after revision 19 April 2005;
first published online 21 April 2005)
Corresponding author I. D. Forsythe: MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK. Email: idf{at}le.ac.uk
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