Tools for manipulating protein condensates at the synapse

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Diverse neural functions are driven by concentrated biomolecular assemblies known as condensates. For example, the postsynaptic density, a structure that anchors neurotransmitter receptors and signaling molecules at the synapse, is thought to form a condensate through a phase-separation process involving multiple highly- networked scaffold molecules. How do the biophysical and material properties of the postsynaptic condensate contribute to synaptic function and plasticity? This project will develop and extend methods that allow inducible formation and/or disruption of biomolecular condensates, applying them in neurons to modulate the material properties of the postsynaptic density while simultaneously assessing synapse structure and function. Aim 1 will develop and apply tools to rapidly increase the rigidity of the postsynaptic density and assess the functional consequences on synaptic structure and plasticity. Aim 2 will focus on methods to inducibly increase the fluidity of the postsynaptic density, reducing the valency of specific scaffold molecules involved in condensate formation. This work will develop general-use tools for manipulating biomolecular condensates throughout the nervous system, with implications for neuronal development, neuropsychiatric diseases, addiction and other brain disorders.