Dirk Isbrandt / Maria A Rüger / Michael Schroeter / Igor Jakovcevski - C 8

Novel roles for HCN/h- and Kv7/M-currents in the development of the cerebral cortex

Abstract

There is increasing evidence that early development of the cerebral cortex is dependent on neuronal activity. Here, we propose that, at the level of neural stem cells (NSCs), two subthreshold voltage-dependent ionic currents, linked to epileptic encephalopathy in human neonates and infants, play a role in early developmental processes, such as proliferation, migration, and differentiation. HCN/h-current (Ih), a nonselective cationic current, and KCNQ/Kv7/M-current (IM), a potassium current, are both voltage-dependent currents with neuromodulatory functions that are associated with transmitter receptors through intracellular signal transduction pathways. We will study mouse models of impaired HCN- or Kv7- subunit function during embryonic development. Expression of a dominant-negative HCN subunit driven by the Emx1 promoter causes severe malformation of the cerebral cortex. Forebrain-specific Kcnq2 knockout results in a milder phenotype characterized by smaller body and brain size. In addition to the analysis of transgenic mice, we will investigate the developmental processes impaired by altered Ih or IM activities using in utero electroporation of control or mutant channel subunits and an in vitro NSC culture system for studying the effects of pharmacological blockade or activation of IM and the blockade of Ih on proliferation, migration, differentiation, and apoptosis. We expect that our results will advance the basic understanding of the mechanisms of brain development, some of which may contribute to the pathogenesis of neurological disorders such as epilepsy.

Clinical/medical relevance and sustainability in disease understanding

This project will promote our understanding of the important regulatory processes during cerebral cortex development. Mutations in ion channel genes studied here in the context of early development are linked to epilepsy syndromes with comorbidities such as autism, ADHD, and cognitive impairment in humans. We expect that studying brain malformations caused by impaired function of these channels in early brain development will lead to a better understanding of the pathogenesis of these disorders


Prof. Dr. med. Dirk Isbrandt

Inst. for Molecular and Behavioral Neuroscience

Prof. Dr. med. Dirk Isbrandt

Principal Investigator C 8

dirk.isbrandt@uni-koeln.de

Work +49 221 478 32732

Institute for Molecular and Behavioral Neuroscience
Kerpener Str. 62
50937 Cologne

Publications - Dirk Isbrandt

Link to PubMed


PD Dr. med. Maria A Rüger

Dept. of Neurology

PD Dr. med. Maria A Rüger

Co-Principal Investigator C 8

adele.rueger@uk-koeln.de

Work +49 221 478 87803

Dept. of Neurology
Kerpener Str. 62
50924 Cologne

Publications - Maria A Rüger

Link to PubMed


Prof. Dr. med. Michael Schroeter

Dept. of Neurology

Prof. Dr. med. Michael Schroeter

Co-Principal Investigator C 8

michael.schroeter@uk-koeln.de

Work +49 221 478 87239

Dept. of Neurology
Kerpener Str. 62
50924 Cologne

Publications - Michael Schroeter

Link to PubMed


Dr. med. Igor Jakovcevski

Inst. for Molecular and Behavioral Neuroscience

Dr. med. Igor Jakovcevski

Co-Principal Investigator C 8

igor.jakovcevski@uk-koeln.de

Work +49 221 478 32734

Institute for Molecular and Behavioral Neuroscience
Kerpener Str. 62
50937 Cologne

Publications - Igor Jakovcevski

Link to PubMed