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: The network effects of knocking down Tnik in these cultures were the most dramatic as shown in Fig. 2. The effect was dramatic enough to be observed by raster plot of the firing frequency recorded by the electrodes of the MEAs (Fig. 2a). The significantly altered parameters included: increased percentage of spikes in bursts, decreased duration of bursts and increased coordination of bursting activity across neurons in the network as reflected by the decreased burst pattern and increased correlation index parameters. All quantitative data is shown in Supplementary Table 2. The burst correlation in particular is of interest because of the connection between schizophrenia and neural network synchrony. In all cases the effect observed becomes significant only after 7 DIV, indicating that the networks remained normal for at least three days after application of the siRNA, and remained significant through the 12th day of culture. The delayed onset of effect after the application of the siRNA could be due to the time it takes for protein to turnover in the cell after new translation has stopped. The 11–12 DIV timepoint is past the expected efficacy of siRNA treatment, and could also suggest the protein turnover “lag” between translation and function. However, it may also indicate irreversible effects to the development of neuronal networks that cannot be compensated at a later time.
Affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK.