title: Ictal activity induced by group I metabotropic glutamate receptor activation and loss of afterhyperpolarizations.
abstract: Exposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxyphenylglycine (DHPG) produces long-lasting changes in network excitability and epileptiform activity in the CA3 region of rat hippocampal slices that continues in the absence of the agonist and includes both interictal and more prolonged ictal-like activity. We evaluated the afterhyperpolarization (AHP) that follows repetitive neuronal firing in neurons exposed to DHPG and related the change in the AHP to the pattern of epileptiform activity. In contrast to neurons from control slices that had a robust AHP following neuronal depolarization and action potential generation, neurons that had been exposed to DHPG displayed a minimal AHP following depolarization. Whole-cell voltage-clamp recordings showed a small outward or transient inward current following a depolarizing pulse in neurons from slices that had been exposed to DHPG while control neurons had a long-lasting outward current. In slices that demonstrated ictal patterns after exposure to DHPG, bath application of 1-ethyl-2-benzimidazolinone (1-EBIO, 1 mM) or 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DCEBIO, 100 microM) which enhance the AHP, suppressed ictal discharges. Whole-cell voltage-clamp recordings demonstrated the return of the medium and slow AHP current in neurons that had transiently been exposed to DHPG when 1-EBIO or DCEBIO was bath-applied. Co-application of either 1-EBIO or DCEBIO with DHPG blocked the induction of epileptiform activity. Transient DHPG exposure caused a long-term suppression of the AHP and ictal patterns of epileptiform activity. 1-EBIO or DCEBIO which re-established both the medium and slow AHP suppressed ictal discharges. These results support the hypothesis that the loss of the AHP contributes to the generation of ictal activity after transient DHPG exposure.
authors.affiliation: Department of Neurology, William S. Middleton Memorial VA Hospital, University of Wisconsin Medical School, Madison, WI 53705, USA.
authors.forename: Yu-Zhen
authors.initials: YZ
authors.lastname: Pan
authors.forename: Linda
authors.initials: L
authors.lastname: Karr
authors.forename: Paul
authors.initials: P
authors.lastname: Rutecki
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D004827:Epilepsy; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: C507351:5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002491:Central Nervous System Agents; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; C079215:3,5-dihydroxyphenylglycine; C102635:1-ethyl-2-benzimidazolinone; D005998:Glycine
references.citation: J Neurophysiol. 2006 Dec;96(6):3028-41
references.pmid: 16971683
references.citation: Neuropharmacology. 2005 Sep;49(3):376-88
references.pmid: 15993438
references.citation: J Neurophysiol. 2004 Nov;92(5):2811-9
references.pmid: 15240770
references.citation: Eur J Pharmacol. 2006 Sep 28;546(1-3):48-53
references.pmid: 16925994
references.citation: J Physiol. 1989 Feb;409:171-90
references.pmid: 2585290
references.citation: J Neurophysiol. 2000 May;83(5):2844-53
references.pmid: 10805682
references.citation: Neuroscience. 1997 Dec;81(4):927-35
references.pmid: 9330356
references.citation: J Neurosci. 2007 Jan 3;27(1):59-68
references.pmid: 17202472
references.citation: Epilepsy Res. 2008 Sep;81(1):14-23
references.pmid: 18495430
references.citation: Biochem J. 2001 Nov 1;359(Pt 3):465-84
references.pmid: 11672421
references.citation: Neuron. 2007 Feb 15;53(4):487-93
references.pmid: 17296551
references.citation: Brain Res. 1973 Mar 30;52:1-17
references.pmid: 4573428
references.citation: J Neurosci. 2009 Mar 18;29(11):3497-507
references.pmid: 19295155
references.citation: J Physiol. 1986 Mar;372:221-44
references.pmid: 2873241
references.citation: Prog Neurobiol. 2002 Apr;66(5):345-53
references.pmid: 12015199
references.citation: Epilepsy Res. 1995 Feb;20(2):125-36
references.pmid: 7750509
references.citation: J Neurosci. 2001 Aug 15;21(16):5925-34
references.pmid: 11487615
references.citation: J Neurophysiol. 1995 Aug;74(2):896-900
references.pmid: 7472393
references.citation: Epilepsy Res. 2003 Mar;53(3):186-95
references.pmid: 12694926
references.citation: Brain Res. 1989 Jul 17;492(1-2):337-46
references.pmid: 2752304
references.citation: J Neurophysiol. 2008 Mar;99(3):1105-18
references.pmid: 18184892
references.citation: J Neurophysiol. 2008 Nov;100(5):2589-604
references.pmid: 18684909
references.citation: J Physiol. 2002 Oct 1;544(Pt 1):29-37
references.pmid: 12356878
references.citation: J Physiol. 2004 Jan 15;554(Pt 2):371-85
references.pmid: 14578486
references.citation: Epilepsy Curr. 2002 May;2(3):81-85
references.pmid: 15309152
references.citation: J Neurosci. 2003 Aug 27;23(21):7873-80
references.pmid: 12944517
references.citation: Brain Res. 2005 Dec 14;1065(1-2):37-46
references.pmid: 16336949
references.citation: J Biol Chem. 2005 Dec 16;280(50):41404-11
references.pmid: 16239218