title: KCC2-deficient mice show reduced sensitivity to diazepam, but normal alcohol-induced motor impairment, gaboxadol-induced sedation, and neurosteroid-induced hypnosis.
abstract: GABA(A) receptors mediate both fast phasic inhibitory postsynaptic potentials and slower tonic extrasynaptic inhibition. Hyperpolarizing phasic GABAergic inhibition requires the activity of neuron-specific chloride-extruding potassium-chloride cotransporter KCC2 in adult CNS. However, the possible role of KCC2 in tonic GABAergic inhibition and the associated behaviors is unknown. Here, we have examined the role of KCC2 in phasic vs tonic GABA inhibition by measuring the behavioral effects of pharmacological agents that presumably enhance phasic vs tonic inhibition in mice that retain 15-20% of normal KCC2 protein levels. These KCC2-deficient mice show decreased sensitivity to diazepam-induced sedation and motor impairment consistent with the reported role for KCC2 in fast hyperpolarizing inhibition. In contrast, the mice exhibit normal responses to low-dose alcohol-induced motor impairment, gaboxadol-induced sedation, and neurosteroid-induced hypnosis; behaviors thought to be associated with tonic GABAergic inhibition. Electrophysiological recordings show that the tonic conductance is not affected. The results suggest that KCC2 activity is more critical for behaviors dependent on phasic than tonic GABAergic inhibition.
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Tornberg
authors.forename: Mikael
authors.initials: M
authors.lastname: Segerstråle
authors.forename: Natalia
authors.initials: N
authors.lastname: Kulesskaya
authors.forename: Vootele
authors.initials: V
authors.lastname: Voikar
authors.forename: Tomi
authors.initials: T
authors.lastname: Taira
authors.forename: Matti S
authors.initials: MS
authors.lastname: Airaksinen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019957:Motor Skills Disorders / Q000139:chemically induced / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects; D027981:Symporters / Q000172:deficiency*; D000096922:K Cl- Cotransporters
chemical_list: D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D003975:Diazepam; D000431:Ethanol; D007555:Isoxazoles; D027981:Symporters; D000096922:K Cl- Cotransporters; C015542:gaboxadol