Cortical Excitability. Evidence for an excitable focal cortical region is sug- gested by an increased expression of Nav1.1 and Nav1.6 selectively at the focal region in the somatosensory cor- tex and only in 5- to 6-month-old WAG/Rij rats.44 Other evidence comes from neurophysiologic studies, both in vitro and in vivo. In vitro studies showed an increased excitability in the somatosensory cortex in WAG/Rij rats: NMDA-sensitive late EPSP led to action potential discharges in 44% of regular bursting cells in deep neocortical layers, vs. 8% in control rats.45 Whole cell patch-clamp recording from layer II–III cortical pyramidal neurons in WAG/Rij rats was complemented by immunohistochemical, Western blot, and PCR studies of HCN1–HCN4 subunits of the Ih channel. The fast component of Ih activation in neurons of WAG/Rij rats showed a 50% decrease in current density, and was four times slower than in neurons of non- epileptic control Wistar rats. The results of Western blot and PCR analysis corresponded to a decreased Ih current. A 34% decrease was found in HCN1 subunit protein levels in the cerebral cortex of WAG/Rij rats as compared to Wistar rats, but HCN1 mRNA expression was not different. The protein and mRNA levels of the other three Ih channel subunits (HCN2–HCN4) were not altered.46 The rapid age-dependent decline in expression of HCN1 channels preceded the onset of SWDs, suggesting that the loss of HCN1 channel expres- sion is inherited rather than acquired.47 An in vivo elec- trophysiologic study in free-moving animals with electrical evoked potentials in the somatosensory and motor cortex in WAG/Rij and in nonepileptic, age- matched control rats confirmed the increased excitabil- ity in the somatosensory cortex since only the epileptic rats showed an increased response toward cortical elec- trical stimulation. Moreover, stimulation induced SWD- like afterdischarges, suggesting not only that the focal area was more excitable, but also that the whole CTC network became more prone to SWDs.40 It has been proposed that this loss of neocortical HCN1 function but also many neurophysiologic and biochemical changes contribute to an increased cortical excitability.48 Besides increased excitability, impairment of inhibitory processes was found in the frontal cortex of WAG/Rij rats in vivo when they were compared to three other rat strains in a paired pulse inhibition paradigm (sensory gating). The amplitude of the auditory evoked potentials toward the second sti- mulus was enhanced,17,2...
