title: Compensatory enhancement of intrinsic spiking upon NKCC1 disruption in neonatal hippocampus.
abstract: Depolarizing and excitatory GABA actions are thought to be important in cortical development. We show here that GABA has no excitatory action on CA3 pyramidal neurons in hippocampal slices from neonatal NKCC1(-/-) mice that lack the Na-K-2Cl cotransporter isoform 1. Strikingly, NKCC1(-/-) slices generated endogenous network events similar to giant depolarizing potentials (GDPs), but, unlike in wild-type slices, the GDPs were not facilitated by the GABA(A) agonist isoguvacine or blocked by the NKCC1 inhibitor bumetanide. The developmental upregulation of the K-Cl cotransporter 2 (KCC2) was unperturbed, whereas the pharmacologically isolated glutamatergic network activity and the intrinsic excitability of CA3 pyramidal neurons were enhanced in the NKCC1(-/-) hippocampus. Hence, developmental expression of KCC2, unsilencing of AMPA-type synapses, and early network events can take place in the absence of excitatory GABAergic signaling in the neonatal hippocampus. Furthermore, we show that genetic as well as pharmacologically induced loss of NKCC1-dependent excitatory actions of GABA results in a dramatic compensatory increase in the intrinsic excitability of glutamatergic neurons, pointing to powerful homeostatic regulation of neuronal activity in the developing hippocampal circuitry.
authors.affiliation: Department of Clinical Neurophysiology, Oulu University Hospital, FI-90230 Oulu, Finland.
authors.forename: Sampsa T
authors.initials: ST
authors.lastname: Sipilä
authors.forename: Kristiina
authors.initials: K
authors.lastname: Huttu
authors.forename: Junko
authors.initials: J
authors.lastname: Yamada
authors.forename: Ramil
authors.initials: R
authors.lastname: Afzalov
authors.forename: Juha
authors.initials: J
authors.lastname: Voipio
authors.forename: Peter
authors.initials: P
authors.lastname: Blaesse
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001569:Benzodiazepines / Q000494:pharmacology; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters / Q000172:deficiency*; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D000096922:K Cl- Cotransporters
chemical_list: D001569:Benzodiazepines; D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C079692:GYKI 53655