Cell type–specific glial networks Glial cells respond to neurotransmitters when nerve cells communicate with each other. Glial cells themselves release gliotransmitters that regulate neural synaptic transmission. Martín et al. studied this reciprocal relationship in a brain region called the dorsal striatum, which has two types of experimentally identifiable neurons and two types of synapses (see the Perspective by Gittis and Brasier). Subpopulations of glial cells selectively responded to the activity of one specific type of neuron. In turn, these specifically activated glial cells signaled only to the same type of neurons but not the other, indicating that glial-nerve signaling is largely cell-type specific. Science , this issue p. 730 ; see also p. 690

Technology Corporation, Japan G protein-coupled signalling is a major cellular mechanism for controlling excitability in central neurons. One of the main targets for this control at post-synaptic membranes are G protein-gated inwardly rectifying K + (GIRK or Kir3) channels, which generate slow inhibitory post-synaptic potentials following the activation of G i/o -protein-coupled receptors (North 1989 Immunoelectron microscopy showed that the subunit composition of GIRK channels in Purkinje cell spines is compartment-dependent. Thus, at extrasynaptic sites GIRK channels are formed by GIRK1/GIRK2/GIRK3, post-synaptic densities contain GIRK2/GIRK3 and dendritic shafts contain GIRK1/ GIRK3. The post-synaptic association of GIRK subunits with GABA B receptors in Purkinje cells is supported by the subcellular regulation of the ion channel and the receptor in mutant mice. At pre-synaptic sites, GIRK channels localized to parallel fibre terminals are formed by GIRK1/GIRK2/GIRK3 and co-localize with GABA B receptors. Consistent with this morphological evidence we demonstrate their functional interaction at axon terminals in the cerebellum by showing that GIRK channels play a role in the inhibition of glutamate release by GABA B receptors. The association of GIRK channels and GABA B receptors with excitatory synapses at both post-and pre-synaptic sites indicates their intimate involvement in the modulation of glutamatergic neurotransmission in the cerebellum.

At synaptic boutons, metabotropic glutamate receptor 7 (mGlu7 receptor) serves as an autoreceptor, inhibiting glutamate release. In this response, mGlu7 receptor triggers pertussis toxin-sensitive G protein activation, reducing presynaptic Ca 2؉ influx and the subsequent depolarization evoked release. Here we report that receptor coupling to signaling pathways that potentiate release can be seen following prolonged exposure of nerve terminals to the agonist L-(؉)-phosphonobutyrate, L-AP4. This novel mGlu7 receptor response involves an increase in the release induced by the Ca 2؉ ionophore ionomycin, suggesting a mechanism that is independent of Ca 2؉ channel activity, but dependent on the downstream exocytotic release machinery. The mGlu7 receptor-mediated potentiation resists exposure to pertussis toxin, but is dependent on phospholipase C, and increased phosphatidylinositol (4,5)-bisphosphate hydrolysis. Furthermore, the potentiation of release does not depend on protein kinase C, although it is blocked by the diacylglycerolbinding site antagonist calphostin C. We also found that activation of mGlu7 receptors translocate the active zone protein essential for synaptic vesicle priming, munc13-1, from soluble to particulate fractions. We propose that the mGlu7 receptor can facilitate or inhibit glutamate release through multiple pathways, thereby exerting homeostatic control of presynaptic function.Metabotropic glutamate receptors belong to the G proteincoupled receptors (GPCRs) 2 superfamily and their eight receptor subtypes (mGlu1-8 receptors) are classified into three major groups. Most group III mGlu receptors (mGlu4, -6, -7, and -8 receptors) are located within the presynaptic active zone (1) where they act as autoreceptors mediating feedback inhibition of glutamate release (2-4). The signaling mechanism initiated by mGlu7 receptors to inhibit neurotransmitter release involves the activation of G i/o proteins that inhibit Ca 2ϩ channels and adenylyl cyclase (5), and probably the release process itself (6). However, mGlu7 receptor signaling is not restricted to these pathways. Thus, transfected mGlu7 receptors expressed in cerebellar granule cells inhibits somatic Ca 2ϩ currents by a mechanism that involves the activation of phospholipase C (PLC) and the hydrolysis of phosphatidylinositol (4,5)-bisphosphate thereby generating inositol trisphosphate that releases Ca 2ϩ from intracellular stores and diacylglycerol (DAG) that activates protein kinase C (PKC) (7). However, one important question that remains to be resolved is whether endogenous mGlu7 receptors at synaptic sites also signal via PLC and if so, what effect such signaling has on release modulation.Phorbol esters, stable analogues of the endogenous product of PLC, DAG, potentiate synaptic transmission by increasing neurotransmitter release (8 -15). DAG signaling at synapses has long been thought to be mediated by PKC and both presynaptic K ϩ and Ca 2ϩ channels, as well as other proteins of the release machinery, have been identified as PKC substrates....

The modulation of calcium channels by metabotropic glutamate receptors (mGluRs) is a key event in the fine-tuning of neurotransmitter release. Here we report that, in hippocampal nerve terminals from adult rats, the inhibition of glutamate release by the group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) is largely mediated by mGluR7. In this preparation, P/Q-type Ca(2+) channels support the major component of glutamate release while the remaining release is supported by N-type Ca(2+) channels. The release associated with P/Q channels was modulated by mGluR7, either in the presence of omega-conotoxin-GVIA or after decreasing the extracellular Ca(2+) concentration [Ca(2+)](o) to abolish the contribution of N-type Ca(2+) channels. Under these conditions, L-AP4 (1 mm) reduced the evoked glutamate release by 35 +/- 2%. This inhibition was largely prevented by pertussis toxin, but it was insensitive to inhibitors of protein kinase C (bisindolylmaleimide) and protein kinase A (H-89). Furthermore, this inhibition was associated with a reduction in the Ca(2+) influx mediated by P/Q channels in the absence of any detectable change in cAMP levels. However, L-AP4 decreased the levels of cAMP in the presence of forskolin. The activation of this additional signalling pathway was very efficient in counteracting the facilitation of glutamate release induced by forskolin. Thus, mGluR7 mediates the inhibition of glutamate release at hippocampal nerve terminals primarily by inhibiting P/Q-type Ca(2+) channels, although augmenting the levels of cAMP reveals the ability of the receptor to decrease cAMP.