Elucidating synapse-specific defects underlying autism
2016 Weatherstone Predoctoral Fellowship
Salt Lake City, Utah
Autism spectrum disorder (ASD) is a synapse disorder. Many genes, cells, and systems are identified as dysfunctional in ASD, but all are thought to ultimately disrupt synapse form and function. Yet despite copious studies, synaptic defects underlying ASD remain unknown. To propel the autism field forward, make sense of the conflicting literature, and rationally design treatments, it is critically important to understand how correct specific synapses develop, and how these specific synapses differ in ASD. This need is exemplified by our research on the autism-linked gene Kirrel3. We discovered Kirrel3 regulates excitatory synapse formation in the mouse hippocampus. Alone, this suggests Kirrel3 null mice should have decreased hippocampal activity. However, we find Kirrel3 regulates connections specifically between DG neurons and inhibitory GABA neurons. This decreases the ratio of excitation and inhibition to CA3 neurons consequently increasing hippocampal activity. Here, I will define the precise role of Kirrel3 in synapse development using 3D electron microscopy to define ultrastructural synaptic defects in Kirrel3 knockout mice. I will also test if disease-associated Kirrel3 missense mutations impair Kirrel3’s synaptic functions. This work will significantly advance our understanding of synaptic defects underlying ASD and give precedent for similar synapse-specific analyses leading to potential development of improved ASD therapies correcting synapse and network imbalances.
Grant Term:2 years
Award Type:Weatherstone Predoctoral Fellowship