PMID- 24780380 OWN - NLM STAT- MEDLINE DCOM- 20150202 LR - 20211203 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 84 DP - 2014 Sep TI - Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures. PG - 1-12 LID - S0028-3908(14)00137-3 [pii] LID - 10.1016/j.neuropharm.2014.04.011 [doi] AB - Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. "Autonomous" CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down-regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Bernard, Paul B AU - Bernard PB AD - Department of Pediatrics, University of Colorado, School of Medicine, CO, USA. FAU - Castano, Anna M AU - Castano AM AD - Department of Pediatrics, University of Colorado, School of Medicine, CO, USA. FAU - Bayer, K Ulrich AU - Bayer KU AD - Neuroscience Graduate Program, University of Colorado, School of Medicine, CO, USA; Department of Pharmacology, University of Colorado, School of Medicine, CO, USA. FAU - Benke, Tim A AU - Benke TA AD - Department of Pediatrics, University of Colorado, School of Medicine, CO, USA; Neuroscience Graduate Program, University of Colorado, School of Medicine, CO, USA; Department of Neurology, University of Colorado, School of Medicine, CO, USA; Department of Pharmacology, University of Colorado, School of Medicine, CO, USA; Department of Otolaryngology, University of Colorado, School of Medicine, CO, USA. Electronic address: tim.benke@ucdenver.edu. LA - eng GR - R01 NS076577/NS/NINDS NIH HHS/United States GR - R01 NS081248/NS/NINDS NIH HHS/United States GR - R01NS076577/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140426 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Calcium Channels, L-Type) RN - 0 (Receptors, Metabotropic Glutamate) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - SIV03811UC (Kainic Acid) SB - IM MH - Animals MH - Calcium Channels, L-Type/metabolism MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors/metabolism MH - Disease Models, Animal MH - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism MH - Hippocampus/*physiopathology MH - Kainic Acid MH - Long-Term Synaptic Depression/drug effects/*physiology MH - MAP Kinase Signaling System/drug effects/physiology MH - Membrane Potentials/drug effects/physiology MH - Proteasome Endopeptidase Complex/metabolism MH - Rats, Sprague-Dawley MH - Receptors, Metabotropic Glutamate/*metabolism MH - Ribosomal Protein S6 Kinases/metabolism MH - Seizures/*physiopathology MH - Signal Transduction/drug effects/physiology MH - Synapses/drug effects/physiology MH - TOR Serine-Threonine Kinases/metabolism MH - Tissue Culture Techniques PMC - PMC4086946 MID - NIHMS598565 OTO - NOTNLM OT - Autism OT - CaMKII OT - Early life seizure OT - Long-term depression OT - Metabotropic glutamate receptor OT - Voltage-gated calcium channels EDAT- 2014/05/02 06:00 MHDA- 2015/02/03 06:00 PMCR- 2015/09/01 CRDT- 2014/05/01 06:00 PHST- 2013/12/20 00:00 [received] PHST- 2014/03/28 00:00 [revised] PHST- 2014/04/14 00:00 [accepted] PHST- 2014/05/01 06:00 [entrez] PHST- 2014/05/02 06:00 [pubmed] PHST- 2015/02/03 06:00 [medline] PHST- 2015/09/01 00:00 [pmc-release] AID - S0028-3908(14)00137-3 [pii] AID - 10.1016/j.neuropharm.2014.04.011 [doi] PST - ppublish SO - Neuropharmacology. 2014 Sep;84:1-12. doi: 10.1016/j.neuropharm.2014.04.011. Epub 2014 Apr 26.