title: Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy.
abstract: Human cortical malformations often result in severe forms of epilepsy. Although the morphological properties of cells within these malformations are well characterized, very little is known about the function of these cells. In rats, prenatal methylazoxymethanol (MAM) exposure produces distinct nodules of disorganized pyramidal-like neurons (e.g., nodular heterotopia) and loss of lamination in cortical and hippocampal structures. Hippocampal nodular heterotopias are prone to hyperexcitability and may contribute to the increased seizure susceptibility observed in these animals. Here we demonstrate that heterotopic pyramidal neurons in the hippocampus fail to express a potassium channel subunit corresponding to the fast, transient A-type current. In situ hybridization and immunohistochemical analysis revealed markedly reduced expression of Kv4.2 (A-type) channel subunits in heterotopic cell regions of the hippocampus of MAM-exposed rats. Patch-clamp recordings from visualized heterotopic neurons indicated a lack of fast, transient (I(A))-type potassium current and hyperexcitable firing. A-type currents were observed on normotopic pyramidal neurons in MAM-exposed rats and on interneurons, CA1 pyramidal neurons, and cortical layer V-VI pyramidal neurons in saline-treated control rats. Changes in A-current were not associated with an alteration in the function or expression of delayed, rectifier (Kv2.1) potassium channels on heterotopic cells. We conclude that heterotopic neurons lack functional A-type Kv4.2 potassium channels and that this abnormality could contribute to the increased excitability and decreased seizure thresholds associated with brain malformations in MAM-exposed rats.
authors.affiliation: Department of Neurological Surgery, The Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Castro
authors.forename: E C
authors.initials: EC
authors.lastname: Cooper
authors.forename: D H
authors.initials: DH
authors.lastname: Lowenstein
authors.forename: S C
authors.initials: SC
authors.lastname: Baraban
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000503:physiopathology; D002828:Choristoma / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D051668:Delayed Rectifier Potassium Channels; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D051669:Shab Potassium Channels; D051672:Shal Potassium Channels; D013003:Somatosensory Cortex / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: D051668:Delayed Rectifier Potassium Channels; C496991:Kcnb1 protein, rat; C497020:Kcnd2 protein, rat; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051669:Shab Potassium Channels; D051672:Shal Potassium Channels; D008746:Methylazoxymethanol Acetate; D019789:Tetraethylammonium; D015761:4-Aminopyridine; C030667:methylazoxymethanol; D011188:Potassium