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The Journal of Neuroscience, April 30, 2008, 28(18):4635-4639; doi:10.1523/JNEUROSCI.0908-08.2008

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Brief Communications
GABAergic Depolarization of the Axon Initial Segment in Cortical Principal Neurons Is Caused by the Na–K–2Cl Cotransporter NKCC1

Stanislav Khirug,^1 * Junko Yamada,^1 * Ramil Afzalov,¹ Juha Voipio,¹ Leonard Khiroug,² and Kai Kaila^1,2

¹Department of Biological and Environmental Sciences and ²Neuroscience Center, University of Helsinki, FIN-00014 Helsinki, Finland

Correspondence should be addressed to Kai Kaila, Department of Biological and Environmental Sciences, University of Helsinki, P.O. Box 65, FIN-00014 Helsinki, Finland. Email: kai.kaila{at}helsinki.fi

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.

Key words: axon initial segment; NKCC1; KCC2; synapse; chloride; caged GABA

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Received Aug. 28, 2007; revised March 27, 2008; accepted March 27, 2008.

Correspondence should be addressed to Kai Kaila, Department of Biological and Environmental Sciences, University of Helsinki, P.O. Box 65, FIN-00014 Helsinki, Finland. Email: kai.kaila{at}helsinki.fi

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