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Regulation of Cortical Circuit Assembly by Syngap1

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Kilinc, Murat

Rumbaugh, Gavin

The Scripps Research Institute, FL

$64,000.00

2 years

Weatherstone Predoctoral Fellowship

Jupiter

Florida

United States

2017

http://www.scripps.edu

https://plu.mx/autismspeaks/grant/autismspeaks-10646

Past research has established pathogenic SYNGAP1 mutations as risk factors for autism spectrum disorder and epilepsy. SynGAP is primarily known as a synaptic protein, and its loss causes abnormally large dendritic spines and LTP deficits. In addition to its effect on synapse physiology, our lab has shown that such mutations result in aberrant dendritic development. However, molecular mechanisms underlying the effect of Syngap1 on dendritic development remain unknown. An important roadblock in the field is that Syngap1 expresses many isoforms with unknown functions.
I hypothesize that Syngap1 regulates dendritic development and synapse physiology via distinct isoforms. In this study, I propose to identify and characterize functions of individual isoforms on dendritic and synaptic development. We will follow this with a systems-level study of novel mouse lines with isoform specific mutations. We will follow these studies, in turn, by dissecting the interaction between specific isoforms and major growth pathways.
Our study will delineate the role of individual domains as they pertain to major wiring processes. It will also reveal the major signaling components required for proper cortical circuit assembly. Elucidating the roles of individual Syngap1 isoforms will enable exploration of aberrant molecular networks involved in ASD with intellectual disability (ID).
By identifying such pathways, this project will advance our understanding of ASD/ID at the molecular and systems level and advance research aimed at identifying therapeutic targets.

Developmental Biology, Cellular Biology, Developmental Biology, Electrophysiology - Synaptic, Microscopy, Confocal, Molecular Biology, Neurobiology, Biology, Etiology/ Risk Factors, Treatment/ Prevention, Mice, Cultured Neurons, Brain Atlas, Brain (genetic Material), Brain Tissue

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