title: Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures.
abstract: Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.
authors.affiliation: Neurobiologie des Processus Adaptatifs, UMR 7102 CNRS, Université Pierre et Marie Curie-Paris 6, 9 quai St Bernard, 75252 Paris Cedex 05, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bessaïh
authors.forename: Laurence
authors.initials: L
authors.lastname: Bourgeais
authors.forename: Carmen I
authors.initials: CI
authors.lastname: Badiu
authors.forename: David A
authors.initials: DA
authors.lastname: Carter
authors.forename: Tibor I
authors.initials: TI
authors.lastname: Toth
authors.forename: Diego
authors.initials: D
authors.lastname: Ruano
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lambolez
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Crunelli
authors.forename: Nathalie
authors.initials: N
authors.lastname: Leresche
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004832:Epilepsy, Absence / Q000235:genetics* / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020646:Intralaminar Thalamic Nuclei / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology; D013003:Somatosensory Cortex / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D020651:Ventral Thalamic Nuclei / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D011412:Propanolamines; D011963:Receptors, GABA-A; C085075:CGP 55845A; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C066430:CGP 35348; D001418:Baclofen