Selective Inhibition of Spontaneous But Not Ca²⁺-Dependent Release Machinery by Presynaptic Group II mGluRs in Rat Cerebellar Slices

Abstract

Glitsch, Maike. Selective inhibition of spontaneous but not Ca 2ϩ -dependent release machinery by presynaptic group II mGluRs in rat cerebellar slices. J Neurophysiol 96: 86 -96, 2006. First published April 12, 2006 doi:10.1152/jn.01282.2005. Two main forms of neurotransmitter release are known: action potential-evoked and spontaneous release. Action potential-evoked release depends on Ca 2ϩ entry through voltage-gated Ca 2ϩ channels, whereas spontaneous release is thought to be Ca 2ϩ -independent. Generally, spontaneous and action potential-evoked release are believed to use the same release machinery to release neurotransmitter. This study shows, using the whole cell patch-clamp technique in rat cerebellar slices, that at the interneuronPurkinje cell synapse activation of presynaptic group II metabotropic glutamate receptors suppresses spontaneous GABA release through a mechanism independent of voltage-gated Ca 2ϩ channels, store-operated Ca 2ϩ channels, and Ca 2ϩ release from intracellular Ca 2ϩ stores, suggesting that the metabotropic receptors target the release machinery directly. Voltage gated Ca 2ϩ channel-independent release following increased presynaptic cAMP production is similarly inhibited by these metabotropic receptors. In contrast, both voltage-gated Ca 2ϩ channel-dependent and presynaptic N-methyl-D-aspartate receptordependent GABA release were unaffected by activation of group II metabotropic glutamate receptors. Hence, the mechanisms underlying spontaneous and Ca 2ϩ -dependent GABA release are distinct in that only the former is blocked by group II metabotropic glutamate receptors. Thus the same neurotransmitter, glutamate, can activate or inhibit neurotransmitter release by selecting different receptors that target different release machineries.

Differential regulation of spontaneous and evoked neurotransmitter release at central synapses

“…Examples of this anomalous regulation include selective inhibition of spontaneous but not Ca 2+ -dependent evoked release by activation of presynaptic group II metabotropic glutamate receptors in rat cerebellar slices [38], specific enhancement of spontaneous miniature excitatory postsynaptic currents (mEPSCs) but not evoked EPSCs in response to BDNF application in immature visual cortical neurons [39], and selective activity-dependent decrease in the frequency of miniature EPSCs triggered by inhibition of DNA methyltransferases, key enzymes that methylate DNA and regulate gene expression [40]. Induction of endoplasmic reticulum stress also causes a dramatic four-fold increase in spontaneous excitatory transmission coupled with only a small increase in evoked neurotransmitter release probability [41].…”

Calcium regulation of spontaneous and asynchronous neurotransmitter release

“…Perhaps other GPCRs play a role; multiple GPCRs modulate spontaneous release [3]. Group II mGluR agonists reduce spontaneous release but have no effect on evoked release of GABA onto Purkinje cells [80]. Likewise activation of GABA B or cannabinoid receptors reduces spontaneous release in the cerebellum [54, 81].…”

Vesicular Zinc Regulates the Ca2+Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

“…Spontaneous and evoked releases have been shown to use distinct pools of vesicles (Sara et al, 2005;Fredj and Burrone, 2009; but see Prange and Murphy, 1999;Groemer and Klingauf, 2007) and be differentially regulated by presynaptic calcium dynamics (Glitsch, 2006). Next, we examined the relationship between the dynamics of intraterminal calcium rise and the presence of the ZnT3/zinc in the vesicles.…”