A synapse is the fundamental structural unit by which neurons communicate. The importance of synapses cannot be overstated as their collective activities impact every moment of our subconscious and conscious mind. Furthermore, synapses are formed and continuously restructured throughout life based on different experiences, which ultimately shapes us as individuals with unique memories, thoughts, skills, and personalities. How the trillions of synapses in a brain are wired into functional neural networks and the mechanisms of experience-dependent synaptic plasticity are important outstanding questions.
We are particularly fascinated by synaptic adhesion proteins, which bind across the synaptic cleft to form a molecular interface between pre- and post-synaptic membranes and also initiate intercellular trans-synaptic signaling. These proteins are at the junction of our genes and experiences and are critical for initiating and stabilizing synaptic changes in a multitude of ways. Our research goal is to understand the molecular logic of how synaptic adhesion proteins orchestrate synaptic formation, modification, and function, and to ultimately provide an explanation for how these events influence behaviors, in particular the aberrant behaviors associated with neuropsychiatric diseases.
The immediate focus of our research is on the neuronally secreted C1q-like family of proteins. The lab studies the biochemical interactions with their pre- and post-synaptic protein binding partners, their synaptic signaling activities, and their eventual behavioral consequences. A priori, their localization in the synaptic cleft almost predestines them to have neuropsychiatric disease relevance. Genetic analyses of C1q-like mutant mice revealed behavioral abnormalities potentially resembling several neuropsychiatric diseases, including ADHD and addiction predisposition. How C1q-like proteins and their binding partners influence synapses and ultimately behaviors is unknown. The techniques used in the lab to answer these questions encompass biochemistry, genetics, cell biology, circuit analysis using viral vectors, and behavioral assays.
C1Q-like proteins are released pre-synaptically from excitatory neurons into the synaptic cleft, where they cross the synaptic cleft and interact with a post-synaptically localized G protein-coupled receptor (GPCR) called ADGRB3 (a.k.a. BAI3). There are two possible mechanisms for how C1Q-like proteins can influence synapses, which are not necessarily mutually exclusive:
1) C1Q-like proteins are ligands that induce the GPCR to initiate intracellular signaling in the post-synaptic spine, and
2) There exists a yet to be discovered pre-synaptic membrane tethered binding partner, thereby creating a trans-synaptic adhesion complex that holds the two sides of the synapse together.
In our recent publication in the FASEB journal, we conducted a screen to identify novel C1QL3 binding partners, which revealed members of the neuronal pentraxin family (NPTX1 and NPTXR). The conclusion was confirmed using quantitative biochemical methods (surface plasmon resonance) to measure the binding affinity. We predict that the neuronal pentraxins are a component in a C1QL-mediated trans-synaptic adhesion complex.
