title: Knockdown of mental disorder susceptibility genes disrupts neuronal network physiology in vitro.
abstract: Schizophrenia and bipolar disorder are common diseases caused by multiple genes that disrupt brain circuits. While great progress has been made in identifying schizophrenia susceptibility genes, these studies have left two major unanswered mechanistic questions: is there a core biochemical mechanism that these genes regulate, and what are the electrophysiological consequences of the altered gene expression? Because clinical studies implicate abnormalities in neuronal networks, we developed a system for studying the neurophysiology of neuronal networks in vitro where the role of candidate disease genes can be rapidly assayed. Using this system we focused on three postsynaptic proteins DISC1, TNIK and PSD-93/DLG2 each of which is encoded by a schizophrenia susceptibility gene. We also examined the utility of this assay system in bipolar disorder (BD), which has a strong genetic overlap with schizophrenia, by examining the bipolar disorder susceptibility gene Dctn5. The global neuronal network firing behavior of primary cultures of mouse hippocampus neurons was examined on multi-electrode arrays (MEAs) and genes of interest were knocked down using RNAi interference. Measurement of multiple neural network parameters demonstrated phenotypes for these genes compared with controls. Moreover, the different genes disrupted network properties and showed distinct and overlapping effects. These data show multiple susceptibility genes for complex psychiatric disorders, regulate neural network physiology and demonstrate a new assay system with wide application.
authors: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK.
authors: Erik J
authors: EJ
authors: MacLaren
authors: Paul
authors: P
authors: Charlesworth
authors: Marcelo P
authors: MP
authors: Coba
authors: Seth G N
authors: SG
authors: Grant
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics*; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D000081410:Germinal Center Kinases; D051528:Guanylate Kinases / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D009415:Nerve Net / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034622:RNA Interference; D012559:Schizophrenia / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C412476:DISC1 protein, human; D000081410:Germinal Center Kinases; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human; C496468:DLG2 protein, human; D051528:Guanylate Kinases