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UID:1027@biotech.technion.ac.il
DTSTART;TZID=Asia/Jerusalem:20210428T170000
DTEND;TZID=Asia/Jerusalem:20220202T164952
DTSTAMP:20220512T124719Z
URL:https://biotech.technion.ac.il/events/using-computational-models-with-
 human-derived-neurons-for-the-investigation-of-cellular-functional-and-mol
 ecular-mechanisms-of-lithium-response-in-bipolar-disorder-2/
SUMMARY:Using computational models with human derived neurons for the inves
 tigation of cellular\, functional\, and molecular mechanisms of lithium re
 sponse in bipolar disorder
DESCRIPTION:Bipolar disorder (BD) affects 1-2% of the worldwide population 
 and is a leading cause of disability and suicide. The complex and heteroge
 neous genetic background of the patients makes human neurons derived from 
 induced pluripotent stem cells (iPSCs) an attractive model since animal mo
 dels do not fully reproduce the complex human genetics and behavior. Using
  functional and molecular assays\, we have shown that human hippocampal ne
 urons derived from BD patients are hyperexcitable with large after-hyperpo
 larizations. Training machine learning algorithms on electrophysiological 
 features that were recorded from the derived neurons enabled an accurate p
 rediction of the patients’ response to lithium 1. The hippocampal neuron
 s that we derived from lithium non-responsive BD patients exhibited a phys
 iological instability\, causing them to easily shift their excitability st
 ate. The neurons alternated between hypoexcitable and hyperexcitable state
 s forming a network that resided in a multi-excitatory state\, suggesting 
 a mechanism that prompts mood episodes 2. A computational model that we de
 veloped of BD neurons recapitulated the hyperexcitability and physiologica
 l instability phenotypes with similar changes to the conductance of the io
 n channels that we have measured 3. RNA sequencing analysis revealed that 
 the Wnt/beta-catenin signaling pathway is severely impaired in the neurons
  derived from the patients that do not respond to lithium. Furthermore\, t
 he severe down regulation of the LEF1 gene was associated with the hyperex
 citability of the neurons and this hyperexcitability was rescued using LEF
 1 shRNAs 4. Overall\, our studies have identified cellular\, functional\, 
 and transcriptional deficits in neurons derived from BD patients and mecha
 nisms for lithium response.\n\nAbstract
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