Characterization of Neuromodulatory Projections and the Role of the Transcription Factor Bcl11a in Focal Cortical Dysplasia

Norisa Meli1, Sandra Blaess1, Albert Becker2, Pentao Liu3, Neal Copeland4

1 Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany
2 Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany
3 The Wellcome Trust Sanger Institute, Cambridge, UK
4 Institute for Academic Medicine, Houston Methodist, USA

Focal Cortical Dysplasias (FCDs) represent a large variety of cortical malformations associated with abnormal cortical layering and/or occurrence of dysmorphic neuronal elements. FCDs are identified as common causes of pharmacoresistant epilepsies and are frequently localized in the frontal lobe. The frontal lobe local circuits are modulated by monoaminergic (dopaminergic, serotonergic and noradrenergic) projections arising from the brain stem. Earlier analysis on modulatory inputs in FCDs of human biopsy specimens reported altered density and distribution of these monoaminergic fibres. Here we perform a comprehensive analysis of the monoaminergic projections in human biopsy samples and in utero electroporation (IUE)-induced FCD mouse models (Tsc1 conditional knock-out and mTOR mutated) to investigate the underlying functional relation of altered modulatory innervations in FCDs. A microarray expression analysis of neuroepithelial lesions with aberrant neuronal elements resembling FCD identified, amongst others, reduced expression of the transcription factor B-cell lymphoma 11a (BCL11A). Loss-of-function studies indicate a crucial role of BCL11A in cell fate specification and migration of cortical neurons. Moreover, coding variants of BCL11A have recently been associated with epileptic encephalopathies and deletions in the BCL11A locus occurred in patients with grey matter abnormalities. We will investigate in an embryonic IUE-mediated (cKO) of BCL11A whether aberrant migration and/or differentiation of neurons resembling FCD features occur. Also, we will scrutinize if the seizure threshold is altered in the cKO mice.