AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus.
Within the area tempestas (AT) in the anterior piriform cortex, unilateral microinfusions of GABA receptor antagonists and glutamate receptor agonists trigger brief episodic limbic seizures. In the present study, we document a synergistic effect of coinfusing bicuculline (GABAA receptor antagonist) with either carbachol (muscarinic receptor agonist) or cyclothiazide (inhibitor of AMPA receptor desensitization) but not with glutamate receptor agonists (AMPA, NMDA or kainate) in the rat AT. In particular, coadministration of bicuculline (118 pmol) with either carbachol (328 pmol) or cyclothiazide (1.2 nmol) triggered continuous self-sustaining seizures (status epilepticus; SE). Cyclothiazide alone did not evoke seizures. Although blockade of NMDA receptors with AP-7 (100 or 500 pmol) prevented episodic seizures evoked by carbachol or bicuculline alone, it was without effect on the continuous seizures evoked by combined treatments. NMDA-insensitive self-sustaining seizures were also evoked by the combination of AMPA and cyclothiazide. Regardless of the mechanism by which SE was evoked, it was prevented only by an AMPA receptor antagonist, NBQX, thus reinforcing the crucial role of AMPA receptors in the transition to SE. Further evidence for AMPA receptor regulation of seizure severity came from the overexpression of the GluR1 AMPA receptor subunit in AT. This resulted in substantially increased severity of bicuculline-evoked seizures that was reversed by focal application of NBQX. Thus, desensitization of AMPA receptors appears to limit the duration and severity of seizure activity, and a failure of this mechanism, or an overabundance of slowly desensitizing AMPA receptors, predisposes to severe and prolonged seizures.
Fornai
Francesco
F
Department of Pharmacology, W215 Research Bldg, 3970 Reservoir Road NW, Georgetown University, Washington, DC 20057, USA.
Busceti
Carla L
CL
Kondratyev
Alexei
A
Gale
Karen
K
D000818:Animals; D001522:Behavior, Animal; D001581:Benzothiadiazines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology* / Q000821:virology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006566:Herpesviridae Infections / Q000150:complications; D008297:Male; D008845:Microinjections / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013226:Status Epilepticus / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology* / Q000821:virology
D001581:Benzothiadiazines; D018679:Cholinergic Agonists; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D018091:Receptors, AMPA; D002217:Carbachol; C004639:cyclothiazide; D001640:Bicuculline