title: GABAergic depolarization of the axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter NKCC1.
abstract: GABAergic terminals of axo-axonic cells (AACs) are exclusively located on the axon initial segment (AIS) of cortical principal neurons, and they are generally thought to exert a powerful inhibitory action. However, recent work (Szabadics et al., 2006) indicates that this input from AACs can be depolarizing and even excitatory. Here, we used local photolysis of caged GABA to measure reversal potentials (E(GABA)) of GABA(A) receptor-mediated currents and to estimate the local chloride concentration in the AIS compared with other cellular compartments in dentate granule cells and neocortical pyramidal neurons. We found a robust axo-somato-dendritic gradient in which the E(GABA) values from the AIS to the soma and dendrites become progressively more negative. Data from NKCC1(-/-) and bumetanide-exposed neurons indicated that the depolarizing E(GABA) at the AIS is set by chloride uptake mediated by the Na-K-2Cl cotransporter NKCC1. Our findings demonstrate that spatially distinct interneuronal inputs can induce postsynaptic voltage responses with different amplitudes and polarities as governed by the subcellular distributions of plasmalemmal chloride transporters.
authors.affiliation: Department of Biological and Environmental Sciences, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Khirug
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: Leonard
authors.initials: L
authors.lastname: Khiroug
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D002034:Bumetanide / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010648:Phenylacetates / Q000494:pharmacology; D010782:Photolysis; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2; D018709:Statistics, Nonparametric; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D010648:Phenylacetates; C578878:Slc12a2 protein, mouse; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; C109231:alpha-carboxy-2-nitrobenzyl gamma-aminobutyrate; C485184:enhanced green fluorescent protein; D002034:Bumetanide; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid