Evidence of altered inhibition in layer V pyramidal neurons from neocortexof kcna1-null mice

Mice lacking the potassium channel subunit KCNA1 exhibit a severe epileptic phenotype beginning at an early postnatal age. The precise cellular physio logical substrates for these seizures are unclear, as is the site of origin . Since KCNA1 mRNA in normal mice is expressed in the neocortex, we asked w hether neurons in the neocortex of three to four week-old Kcnal-null mutant s exhibit evidence of hyperexcitability. Layer V pyramidal neurons were dir ectly visualized in brain slices with infrared differential-interference co ntrast microscopy and evaluated with cellular electrophysiological techniqu es. There were no significant differences in intrinsic membrane properties and action potential shape between Kcnal-null and wild-type mice, consisten t with previous findings in hippocampal slice recordings. However, the freq uency of spontaneous post-synaptic currents was significantly higher in Kcn al-null compared to wild-type mice. The frequency of spontaneous inhibitory post-synaptic currents and miniature (action-potential-independent) inhibi tory post-synaptic currents was also significantly higher in Kcnal-null com pared to wild-type mice. However, the frequency of spontaneous and miniatur e excitatory post-synaptic currents was not different in these two groups o f animals. Comparison of the amplitude and kinetics of miniature inhibitory and excitatory post-synaptic currents revealed differences in amplitude, r ise time and half-width between Kcnal-null and wild-type mice. Our data ind icate that the inhibitory drive onto layer V pyramidal neurons is increased in Kcnal knockout mice, either directly through an increased spontaneous r elease of GABA from presynaptic terminals contacting layer V pyramidal neur ons, or an enhanced excitatory synaptic input to inhibitory interneurons. ( C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.