PMID- 22326967 OWN - NLM STAT- MEDLINE DCOM- 20121127 LR - 20131121 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 207 DP - 2012 Apr 5 TI - Glutamate transporters control metabotropic glutamate receptors activation to prevent the genesis of paroxysmal burst in the developing hippocampus. PG - 25-36 LID - 10.1016/j.neuroscience.2012.01.036 [doi] AB - Metabotropic glutamate receptors (mGluR) can control neuronal excitability by modulating several ionic channels. In hippocampal pyramidal cells, groups I/II mGluR are located extrasynaptically, suggesting that their endogenous activation is dependent on the glutamate clearance rate and therefore on excitatory amino-acid transporters (EAAT) efficiency. Deficiency of glutamate uptake can generate seizures in rodents and has been suggested as a mechanism of seizure generation in some human epileptic syndromes. However, the cellular mechanisms linking EAAT dysfunction and pathological cortical activities remain elusive. Here, we investigate the possible role of mGluR on paroxysmal burst of multiple unit activities (MUA) generated in the CA1 region of developing hippocampal slices using an EAAT inhibitor, TBOA. These bursts are generated by a synaptic release of glutamate and involve extrasynaptic NMDA receptors (NMDAR) activated by transmitter spillover. Here, we show that postsynaptic mGluR (groups I/II) are tonically activated by the rise in ambient glutamate concentration after EAAT inhibition and strongly contribute to paroxysmal burst genesis. The inhibition of mGluR with broad spectrum antagonists or addition of a glutamate scavenger strongly reduced the occurrence of paroxysmal burst and the frequency/number of MUA during the burst. Moreover, this endogenous activation of groups I/II mGluR leads to (i) the reduction of the slow afterhyperpolarization current (I(sAHP)), increasing the firing pattern of pyramidal cells, and (ii) the potentiation of extrasynaptic NMDAR-mediated responses, enabling glutamate spillover to generate a suprathreshold depolarization for several seconds. Our data show that an insufficient buffering of extracellular glutamate enables a cross talk between groups I/II mGluR and NMDAR, which, combined with a decrease of I(sAHP), leads to the hyperexcitability of the hippocampal network, facilitating the genesis of epileptical-like activity in response to glutamate release. These findings highlight the importance of the control exerted by EAAT on mGluR. CI - Copyright (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Molinari, F AU - Molinari F AD - Inserm, Unite 901, Marseille, 13009, France. FAU - Cattani, A A AU - Cattani AA FAU - Mdzomba, J B AU - Mdzomba JB FAU - Aniksztejn, L AU - Aniksztejn L LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120126 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Receptors, Metabotropic Glutamate) RN - 0 (Vesicular Glutamate Transport Proteins) RN - 3KX376GY7L (Glutamic Acid) SB - IM MH - Animals MH - Animals, Newborn MH - Epilepsy/drug therapy/metabolism/*prevention & control MH - Epilepsy, Temporal Lobe/drug therapy/metabolism/prevention & control MH - Female MH - Glutamic Acid/*physiology MH - Hippocampus/growth & development/*metabolism/physiopathology MH - Male MH - Organ Culture Techniques MH - Rats MH - Rats, Wistar MH - Receptors, Metabotropic Glutamate/agonists/*metabolism/physiology MH - Synaptic Transmission/drug effects/*physiology MH - Vesicular Glutamate Transport Proteins/antagonists & inhibitors/*physiology EDAT- 2012/02/14 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/02/14 06:00 PHST- 2011/11/21 00:00 [received] PHST- 2011/12/23 00:00 [revised] PHST- 2012/01/19 00:00 [accepted] PHST- 2012/02/14 06:00 [entrez] PHST- 2012/02/14 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - S0306-4522(12)00083-8 [pii] AID - 10.1016/j.neuroscience.2012.01.036 [doi] PST - ppublish SO - Neuroscience. 2012 Apr 5;207:25-36. doi: 10.1016/j.neuroscience.2012.01.036. Epub 2012 Jan 26.