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Elucidating the biophysical mechanisms of latrophilin activation in excitatory synapse formation

Illustration of a neuron extending a growth cone

Synapse formation in the brain is an intricately organized process that results in precisely wired networks of neurons. These networks mediate human cognition, but how synapses are formed and maintained is poorly understood. Latrophilins, a class of postsynaptic adhesion G-protein coupled receptors, are necessary for synapse formation in specific regions of the brain and have been linked to multiple neuropsychiatric diseases. Despite the crucial role of latrophilins in synapse formation, little is known about how these molecules direct synapse formation. The leading hypothesis suggests that presynaptic latrophilin ligands may bind to postsynaptic latrophilins and exert mechanical force on latrophilins to trigger signals that instruct synapse formation. However, this mechanism of activation has not been explicitly demonstrated. Moreover, the effects of mechanical force on latrophilin signaling and synapse formation are unknown. Our interdisciplinary team comprising a biophysicist/chemical engineer (Dunn) and a molecular neurobiologist (Südhof) proposes to study the effects of mechanical force on latrophilin signaling and its implications for synapse formation. The results of this highly interdisciplinary project will test the innovative hypothesis that molecular-scale mechanical signals sculpt synapse formation and will shed light on how latrophilin signaling regulates synaptogenesis in the context of both neurodevelopment and neuropsychiatric disease.

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