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Deciphering the mechanism of Kirrel3-mediated synapse formation ‎

Summer 2023

Project Background

Synapses are specialized cell junctions critical for all brain functions. In the brain, there are hundreds ‎of different types of synapses, however; little is known about the molecules that specify the ‎formation of different types of synapses. Our lab identified a molecule called Kirrel3 that is necessary ‎for the formation of one very specific type of synapse in the hippocampus, a brain region critical for ‎learning and memory. This synapse connects DG excitatory neurons to GABAergic inhibitory ‎neurons. Mice that are missing Kirrel3 fail to form these synapses and we showed that this causes a ‎severe imbalance of activity in the hippocampus. Now that we know Kirrel3 is an important molecule ‎for brain development, we aim to understand more about how it works. This includes where it ‎localizes in the neuron, what proteins it interacts with, and whether Kirrel3 functions on the pre ‎and/or postsynaptic side (dendrites vs axons). This work is also clinically relevant because mutations ‎and copy number variations in Kirrel3 are associated with Autism and intellectual disability in ‎humans. Thus, our results have potential to help understand the causes of these disorders and could ‎led to new drug treatments in the future. ‎

Student Role

The goal of this project is to analyze synapse formation in transgenic mice in which Kirrel3 is ‎selectively deleted from different types of neurons (presynaptic vs postsynaptic). Synapses will be ‎analyzed by light and electron microscopy using advanced software. The SPUR student will have their ‎own desk in the main lab and work directly with a graduate student. We generally operate under a ‎system in which the student will observe a technique first, then conduct the technique with a lab ‎mentor helping, and then try the technique on their own. Students will observe mouse surgeries to ‎deliver viral vectors in mice. Students will then gain hands on experience sectioning mouse brains, ‎staining sections, imaging those sections on a super-resolution confocal microscope, and analyzing ‎the fluorescent images in 3D using NeuroLucida360 Software. Students will also have a chance to ‎work with a large electron microscope dataset that is in the lab. Here, they will use specialized ‎software to reconstruct synapses in 3D from the electron micrographs. All the tools including mice, ‎virus, microscope, and software are ready and available in our lab. In addition, students will gain ‎familiarity with reading the primary literature, and will be able to learn about and observe many other ‎molecular, imaging, and mouse behavioral techniques going on in the lab. ‎

Student Learning Outcomes and Benefits

This project consists of a broad range of tools and concepts that involves molecular biology, genetics, ‎neuroscience, and data analysis. Thus, the technical skills and biological concepts students learn will ‎be applicable to almost any scientific direction or field the student chooses to pursue. More ‎fundamentally, the experience should help students learn to think critically and work as a team. I am ‎the current director of the Neuroscience PhD program and participate in medical school teaching. ‎Thus, I aspire to provide undergrads with valuable insight to graduate and medical school. If possible, ‎the student's work could lead to authorship in a future publication. In fact, every paper published ‎from our lab thus far has undergraduate authors. In addition, several past lab members have gone ‎on to successful careers in biotech and teaching positions so we can connect students to alumni with ‎interests in those areas. Importantly, undergraduate research is naturally exploratory and is a great ‎way to see if science is a potential career. ‎

Megan Williams

Associate Professor
Neurobiology & Anatomy

Every student is unique so one size does not fit all. Two important steps in the beginning of a mentoring relationship are to listen to a student's goals and then ask them what they think they need to succeed.