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Impaired Cl^– Extrusion in Layer V Pyramidal Neurons of Chronically Injured Epileptogenic Neocortex

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California

Submitted 16 July 2004; accepted in final form 23 November 2004

In the mature brain, the K⁺/Cl^– cotransporter KCC2 is important in maintaining low [Cl^–]_i, resulting in hyperpolarizing GABA responses. Decreases in KCC2 after neuronal injuries result in increases in [Cl^–]_i and enhanced neuronal excitability due to depolarizing GABA responses. We used the gramicidin perforated-patch technique to measure E_Cl (E_GABA) in layer V pyramidal neurons in slices of partially isolated sensorimotor cortex of adult rats to explore the potential functional consequence of KCC2 downregulation in chronically injured cortex. E_GABA was measured by recording currents evoked with brief GABA puffs at various membrane potentials. There was no significant difference in E_Cl between neurons in control and undercut animals (–71.2 ± 2.6 and –71.8 ± 2.8 mV, respectively). However, when loaded with Cl^– by applying muscimol puffs at 0.2 Hz for 60 s, neurons in the undercut cortex had a significantly shorter time constant for the positive shift in E_Cl during the Cl^– loading phase (4.3 ± 0.5 s for control and 2.2 ± 0.4 s for undercut, P < 0.01). The positive shift in E_Cl 3 s after the beginning of Cl^– loading was also significantly larger in the undercut group than in the control, indicating that neurons in undercut cortex were less effective in maintaining low [Cl^–]_i during repetitive activation of GABA_A receptors. Application of furosemide eliminated the difference between the control and undercut groups for both of these measures of [Cl^–]_i regulation. The results suggest an impairment in Cl^– extrusion resulting from decreased KCC2 expression that may reduce the strength of GABAergic inhibition and contribute to epileptogenesis.

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