The brain contains billions of cells called neurons that wire together into an amazingly complicated circuit. During brain development, neurons form synapses, which are specialized inter-neuronal connections crucial for sending and receiving information. In theory, synapses can form anywhere one neuron contacts another neuron but, in actuality, synapses only form at a small percent of these sites. This feature generates specificity in neural circuits and is essential for proper brain function. Our experiments are aimed at understanding two main questions. 1: How do neurons recognize their correct synaptic partners during development? 2: After an appropriate partner neuron is identified what signals initiate construction of the correct type of synapse? To accomplish these scientific goals, the lab uses a variety of molecular techniques including transgenics, viruses, biochemistry, light and electron microscopy.
Synapses and Disease
It is now clear that many neurodevelopmental and psychiatric disorders are not caused by huge malformations of the brain but instead by subtle morphological or functional changes in specific types of synapses. Many genes involved in synapse development, including the cadherins and Kirrels, are linked to neurological disorders by genome-wide associational studies in humans but the cellular basis of how these genes may cause disease remain virtually unknown. A major goal of our lab research is understanding the cellular mechanisms by which disease-associated genes impact synaptic development.
Understanding Kirrel3 function in synapses and circuits
Kirrel3 is a cell adhesion molecule and mutations in the Kirrel3 gene are associated with autism and intellectual disabilities. Our lab is working to understand the function of Kirrel3 in the developing brain. We discovered that Kirrel3 is required for normal formation of mossy fiber filopodia, which are synaptic structures connecting excitatory DG neurons to GABAergic inhibitory neurons. These structures are important regulators of feed-forward inhibition in the hippocampus and consistent with this, the loss of Kirrel3 causes over-excitation of hippocampal neurons. We are now investigating the precise synaptic defects caused by Kirrel3 loss and elucidating Kirrel3 signaling mechanisms.
Cadherins and Synapse formation
How do cells communicate with each other to identify suitable synaptic partners? We hypothesize that differentially-expressed, cell adhesion molecules capable of spanning cell membranes play a role in this process. This lead to identification of cadherin-9, a cell adhesion molecule expressed exclusively by DG and CA3 neurons that is not present on CA1 neurons. In vitro and in vivo experiments revealed that reducing cadherin-9 expression severely affects the formation of DG synapses but does not affect other types of synapses. Ongoing experiments are aimed at understanding how cadherin-9 regulates this process and investigating the role of other cadherins in synapse formation.
Neurobiology of suicide
In collaboration with Dr. Hilary Coon’s lab at Utah, we are working to identify cellular and synaptic changes associated with increased risk of suicide. This is an exciting new project to translate our expertise in model systems to a uniquely human brain disorder – look for updates!