Chronic Dysfunction of Astrocytic Inwardly Rectifying K+ Channels Specific to the Neocortical Epileptic Focus After Fluid Percussion Injury in the Rat

Stewart TH, Eastman CL, Groblewski PA, Fender SJ, Verley DR, Cook DG, D'Ambrosio R. Chronic dysfunction of astrocytic inwardly rectifying K+ channels specific to the neocortical epileptic focus after fluid percussion injury in the rat. J Neurophysiol 104: 3345-3360, 2010. First published September 22, 2010; doi:10.1152/jn.00398.2010. Astrocytic inwardly rectifying K+ currents (I-KIR) have an important role in extracellular K+ homeostasis, which influences neuronal excitability, and serum extravasation has been linked to impaired K-IR-mediated K+ buffering and chronic hyperexcitability. Head injury induces acute impairment in astroglial membrane I-KIR and impaired K+ buffering in the rat hippocampus, but chronic spontaneous seizures appear in the perilesional neocortex-not the hippocampus-in the early weeks to months after injury. Thus we examined astrocytic K-IR channel pathophysiology in both neocortex and hippocampus after rostral parasaggital fluid percussion injury (rpFPI). rpFPI induced greater acute serum extravasation and metabolic impairment in the perilesional neocortex than in the underlying hippocampus, and in situ whole cell recordings showed a greater acute loss of astrocytic I-KIR in neocortex than hippocampus. I-KIR loss persisted through 1 mo after injury only in the neocortical epileptic focus, but fully recovered in the hippocampus that did not generate chronic seizures. Neocortical cell-attached recordings showed no loss or an increase of I-KIR in astrocytic somata. Confocal imaging showed depletion of KIR4.1 immunoreactivity especially in processes-not somata-of neocortical astrocytes, whereas hippocampal astrocytes appeared normal. In naive animals, intracortical infusion of serum, devoid of coagulation-mediating thrombin activity, reproduces the effects of rpFPI both in vivo and at the cellular level. In vivo serum infusion induces partial seizures similar to those induced by rpFPI, whereas bath-applied serum, but not dialyzed albumin, rapidly silenced astrocytic K-IR membrane currents in whole cell and cell-attached patch-clamp recordings in situ. Thus both acute impairment in astrocytic I-KIR and chronic spontaneous seizures typical of rpFPI are reproduced by serum extravasation, whereas the chronic impairment in astroglial I-KIR is specific to the neocortex that develops the epileptic focus.