Membrane transporters regulating inhibitory neurotransmitter signaling in health and disease
A.J. Moorhouse,1,2 M. Watanabe2 and J. Nabekura,2 1School of Medical Sciences, The University of New South
Wales, NSW 2052, Australia and 2National Institute for Physiological Sciences (NIPS), Okazaki 444-8585,

The efficacy of inhibitory signalling at GABA and glycinergic synapses depends on a number of factors including the permeability properties of the GABA and glycine-activated receptor channels, and also theelectrochemical gradients for the ions that permeate through these channels. The chloride ion (Cl−) is mostpermeant through these channels. The neuronal isoform of the K+-Cl− cotransporter (KCC2) is a majordeterminant of the intracellular Cl− concentration in neurons, and hence a key determinant of the equilibriumpotential for Cl−. The expression levels and function of KCC2 has a large impact on GABA responses. Theconversion of GABAA receptor responses from depolarizing to hyperpolarizing that occurs in some neuronsduring development is due to an upregulation of KCC2 expression. More recent data has indicated that a rangeof neuronal injuries and stress applied to the adult nervous system, both in vivo and in vitro, results in loss ofKCC2 transport and a reversion of GABA responses towards a depolarizing phenotype (Moorhouse &Nabekura, 2011). This downregulation occurs in two stages, an early phase of loss of function and a later phasewhere expression levels decrease (Wake et al., 2007). The early phase is associated with reduced tyrosinephosphorylation of KCC2, which is needed for robust transport function and a punctuate distribution in theplasma membrane (Watanabe et al., 2009).
To further address the functional and cellular consequences of KCC2 expression on GABAergic responses and neuronal inhibition we have utilized a conditional transgenic mouse in which KCC2 expression is under thecontrol of a tetracycline responsive element. Expression levels of KCC2 are increased by withdrawal ofdoxyclycline (DOX) from the diet. Neuronal inhibition was evaluated by susceptibility of mice to induction ofstatus epilepticus (SE) in response to systemic injection of pilocarpine or kainic acid. All procedures wereapproved by the Ethics Review Committee for Animal Experimentation of the National Institutes for NaturalSciences. Systemic injection of pilocarpine (290-400 mg/kg) resulted in SE in four out of 6 control transgenicmice (with normal KCC2) and that was associated with some modest subsequent histological sequelae. SE wasstopped after about 1 hour by diazepam (10-20 mg/kg, ip). The incidence of SE was reduced in mice in whichDOX had been withdrawn from the diet to upregulate KCC2. A ramp-up dosing schedule using kainic acid(25-35 mg/kg, ip) induced SE with greater reproducibility and less mortality. Fiv e out of five control mice (withDOX) had SE that was associated with typically six to ten stage 5 seizures in each mouse. When DOX waswithdrawn from the diet prior to testing (to upregulate KCC2 expression), none of an additional five miceinjected with kainic acid (30-50 mg/kg) showed any SE, and only one mouse had any stage 5 seizures. Henceswitching on KCC2 is strongly preventing seizures and SE in vivo. Preliminary data in hippocampal slicesisolated from DOX-on (control) and DOX-off (KCC2 upregulation) mice suggests only modest changes in thesensitivity of the population spike field potential to inhibition by the GABA receptor agonist muscimol. The datademonstrate that upregulating KCC2 enhances neuronal inhibition during seizure activity, but may not causemajor changes in basal levels of neuronal inhibition in quiescent neuronal circuits.
Moorhouse AJ, Nabekura J. (2011) Cellular Mechanisms of Neuronal Cl- Homeostasis and its Modulation by Neuronal Injury. In Inhibitory Synaptic Plasticity. Eds. Maffei A, Woodin MA. ContemporaryNeuroscience Series. Springer, Ch. 9, pp. 123-136.
Wake H, Watanabe M, Moorhouse AJ, Kanematsu T, Horibe S, Matsukawa N, Asai K, Ojika K, Hirata M, Nabekura J. (2007). Early changes in KCC2 phosphorylation in response to neuronal stress result in
functional downregulation. Journal of Neuroscience 27, 1642-1650.
Watanabe M, Wake H, Moorhouse AJ, Nabekura J. (2009) Clustering of neuronal K+-Cl−-cotransporters in lipid rafts by tyrosine phosphorylation. Journal of Biological Chemistry 284, 27980-27988.
Proceedings of the Australian Physiological Society


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