Ictal activity induced by group I metabotropic glutamate receptor activation and loss of afterhyperpolarizations.
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.
Pan
Yu-Zhen
YZ
Department of Neurology, William S. Middleton Memorial VA Hospital, University of Wisconsin Medical School, Madison, WI 53705, USA.
Karr
Linda
L
Rutecki
Paul
P
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*
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
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