Hippocampal heterotopia lack functional kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy

Human cortical malformations often result in severe forms of epilepsy. Alth ough the morphological properties of cells within these malformations are w ell characterized, very little is known about the function of these cells. In rats, prenatal methylazoxymethanol (MAM) exposure produces distinct nodu les of disorganized pyramidal-like neurons (e.g., nodular heterotopia) and loss of lamination in cortical and hippocampal structures. Hippocampal nodu lar heterotopias are prone to hyperexcitability and may contribute to the i ncreased seizure susceptibility observed in these animals. Here we demonstr ate that heterotopic pyramidal neurons in the hippocampus fail to express a potassium channel subunit corresponding to the fast, transient A-type curr ent. In situ hybridization and immunohistochemical analysis revealed marked ly reduced expression of Kv4.2 (A-type) channel subunits in heterotopic cel l regions of the hippocampus of MAM-exposed rats. Patch-clamp recordings fr om visualized heterotopic neurons indicated a lack of fast, transient (I-A) -type potassium current and hyperexcitable firing. A-type currents were obs erved on normotopic pyramidal neurons in MAM-exposed rats and on interneuro ns, CA1 pyramidal neurons, and cortical layer V-VI pyramidal neurons in sal ine-treated control rats. Changes in A-current were not associated with an alteration in the function or expression of delayed, rectifier (Kv2.1) pota ssium channels on heterotopic cells. We conclude that heterotopic neurons l ack functional A-type Kv4.2 potassium channels and that this abnormality co uld contribute to the increased excitability and decreased seizure threshol ds associated with brain malformations in MAM-exposed rats.