The anticonvulsant lamotrigine enhances Ih in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy.

Alterations of the hyperpolarization activated nonselective cation current (Ih) are associated with epileptogenesis. Accordingly, the second-generation antiepileptic drug lamotrigine (LTG) enhances Ih in rodent hippocampus. We directly evaluated here whether LTG fails to enhance Ih in neocortical slices from patients with pharmacoresistant epilepsy. With somatic current clamp recordings we observed that LTG depolarized the membrane potential, decreased the input resistance and increased the "sag" in human layer 2/3 neocortical pyramidal neurons when confounding IKir was blocked. In subsequent voltage clamp recordings we confirmed a LTG induced increase of Ih that was qualitatively similar to the one we found in rat neocortical and hippocampal pyramidal neurons. This increase is sufficient to curtail single excitatory postsynaptic potentials (EPSPs) and reduces their temporal summation in human neocortical pyramidal neurons under physiological conditions, i.e. without blocking any other currents, as estimated by sharp microelectrode recordings. Taken together LTG increases Ih and thereby alters neuronal excitability, even in neurons of pharmacoresistant patients. However, whether this increase fully countervails the deficits of Ih in epileptic patients, remains elusive.