title: Reduced tonic inhibition after stroke promotes motor performance and epileptic seizures.
abstract: Stroke survivors often recover from motor deficits, either spontaneously or with the support of rehabilitative training. Since tonic GABAergic inhibition controls network excitability, it may be involved in recovery. Middle cerebral artery occlusion in rodents reduces tonic GABAergic inhibition in the structurally intact motor cortex (M1). Transcript and protein abundance of the extrasynaptic GABAA-receptor complex α4β3δ are concurrently reduced (δ-GABAARs). In vivo and in vitro analyses show that stroke-induced glutamate release activates NMDA receptors, thereby reducing KCC2 transporters and down-regulates δ-GABAARs. Functionally, this is associated with improved motor performance on the RotaRod, a test in which mice are forced to move in a similar manner to rehabilitative training sessions. As an adverse side effect, decreased tonic inhibition facilitates post-stroke epileptic seizures. Our data imply that early and sometimes surprisingly fast recovery following stroke is supported by homeostatic, endogenous plasticity of extrasynaptic GABAA receptors.
authors.affiliation: Hans-Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jaenisch
authors.affiliation: Institute of Human Genetics, Jena University Hospital, D-07743 Jena, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Liebmann
authors.affiliation: Hans-Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Guenther
authors.affiliation: Institute of Human Genetics, Jena University Hospital, D-07743 Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Hans-Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Frahm
authors.affiliation: Hans-Berger Department of Neurology, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Otto W
authors.initials: OW
authors.lastname: Witte
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000502:physiology*; D020869:Gene Expression Profiling; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D009043:Motor Activity; D009046:Motor Neurons / Q000502:physiology*; D020543:Proteome / Q000032:analysis; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012038:Regeneration; D012640:Seizures; D020521:Stroke / Q000150:complications* / Q000473:pathology*; D027981:Symporters / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D018698:Glutamic Acid; D020543:Proteome; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D027981:Symporters; D000096922:K Cl- Cotransporters