Knockdown of mental disorder susceptibility genes disrupts neuronal network physiology in vitro.
Bottom Line: 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.
Affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK.Show MeSH
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Mentions: During the first 12 days in control cultures, a dramatic transition from silent neurons to active synchronized cultures was observed as an increase in both the number of spikes recorded each day as well as an increase in the number of electrodes recording bursts (Fig. 1c). The MEA recordings allowed quantitation of the following seven parameters of neural network activity that were used to observe the phenotypic effects of the gene knockdowns: i) total spikes, ii) % of spikes in bursts, iii) burst rate, iv) burst duration, v) burst pattern, vi) network size and vii) correlation index (summarized in Fig. 1a). These seven parameters have a high degree of information content describing the activity of the developing neuronal networks, and allow the effect of an siRNA to be determined in multiple dimensions and therefore facilitate the direct comparison of genes with disparate cellular functions. A summary “barcode” of the knockdown results is presented in Fig. 3 showing parameters that are significantly increased or decreased by the knockdown of each gene at each DIV measured. In addition to this summary barcode, the detailed measurements for each parameter are reported for each of the five timepoints in culture (Supplementary Tables 2–5).
Affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK.