Dynamics of the Structure-Function Relationship at Single Postsynaptic Densities

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DESCRIPTION (provided by applicant): Neurons communicate information across networks in the brain by forming specialized connections called synapses. The function of individual synapses is key to understanding molecular mechanisms of learning and memory and the pathology of synapse function in disease. In particular, pathological changes in the function of glutamatergic synapses are found in psychiatric disorders like schizophrenia and developmental disorders such as autism. Excitatory synapses generally form on small structures called spines, which protrude from the dendrite of the postsynaptic neuron. The principle postsynaptic specialization is a prominent postsynaptic density (PSD), a complex protein network that anchors glutamate receptors across from sites of neurotransmitter release, recruits signal transduction molecules, and connects to trans-synaptic adhesion complexes. Our laboratory has recently described coordinated rearrangement of the PSD structural scaffold in living neurons. PSD morphological dynamics occur rapidly, on a time scale of seconds to minutes, and are regulated by acute changes in synaptic activity. Because precise alignment of presynaptic glutamate release sites with postsynaptic receptors is a critical determinant of synaptic transmission, PSD morphological changes may have important functional consequences. This proposal combines live-cell fluorescent microscopy with electrophysiology and glutamate photolysis to test whether PSD morphological dynamics regulate synaptic transmission and plasticity and whether individual PSD reshaping behavior is set by synapse strength. This proposal extends beyond existing measures of spine morphology by directly imaging an integral synapse structure. Furthermore, it tests new mechanisms for regulating synaptic function driven by PSD morphological dynamics. Knowledge gained from these experiments will extend our understanding of the molecular mechanisms of learning and memory and help to define new strategies for diagnosing, treating, and ameliorating the burden of mental illnesses. A broad range of cognitive disorders and neurological diseases involve a disruption of communication between cells in the brain. The experiments proposed here help illuminate fundamental mechanisms of how these cells communicate with one another, and how they store information through altering the strength of communication over both short and long time scales. Such information will be essential to finding the cause of mental disorders and to designing new prevention, diagnosis, and treatment strategies to improve public health.