Synapses are specialized neuronal junctions required for nearly all neurotransmission in the brain. Most synapses contain many of the same basic molecular components but there are also specificity molecules that instruct neurons to make different types of synapses with different types of synaptic partners. Thus far, research has largely focused on understanding basic molecules found at all synapses and we have little mechanistic understanding of how neurons develop specificity. Nonetheless, mutations in putative synaptic specificity molecules are emerging as key susceptibility genes for cognitive disorders. In particular, mutations in the gene Kirrel3 are repeatedly found in patients with intellectual disabilities but the role of Kirrel3 in synapse formation in the mammalian brain has not been investigated. Here, we present evidence that Kirrel3 is a novel synaptic specificity molecule at hippocampal mossy fiber synapses. In this proposal, we will define the role of Kirrel3 in mossy fiber synapse formation at an ultrastructural level, elucidate Kirrel3 signaling mechanisms, and its role in learning-dependent synaptic plasticity. Importantly, we will determine whether Kirrel3 point mutations identified in patients with autism and intellectual disability have an attenuated synaptic function. Our results will increase our understanding in several intersecting areas of neuroscience including the cellular basis of neurological disorders, learning and memory, and molecular mechanisms of synaptic specificity.
Alterations in the Kirrel3 gene are associated with autism, intellectual disability, and Jacobsen's syndrome. By understanding how Kirrel3 regulates synapse form and function, our research has potential to define cellular mechanisms contributing to these complex psychiatric disorders and eventually lead to their treatment.