A long-term objective of my laboratory is to understand the molecular mechanisms underlying signaling in the brain, especially as it relates to higher brain functions and disease states. In vertebrates, processing of visual information-how details are extracted and recombined to form our perceptions-depends critically on the local circuitry in layers 2/3 of the visual cortex. Although a variety of details are required to define this circuitry, our work focuses on the dynamic factors regulating the excitatory (glutamatergic) pyramidal inputs to inhibitory interneurons, focusing primarily on postsynaptic mechanisms. In particular, we are interested in how protein-protein interactions can affect the gating properties of glutamate receptors. To do so, we will take advantage of heterologous expression systems to study mechanisms of interaction between glutamate receptors and intracellular proteins and how these interactions affect channel function and use paired recordings from synaptically connected (pyramidal-to-interneuron) cells in layers 2/3 to study how these protein-protein interactions directly affect synaptic amplitudes and their frequency dependence. Specifically, we will address (1) The mechanism of synapse-associated protein 97 (SAP97) interaction with AMPAR GluR-A channels, specifically as it relates to changing their biophysical properties. Preliminary data indicate that SAP97 alters the gating properties of GluR-A AMPARs, and experiments proposed here will define the molecular basis for these novel actions providing fundamental insights into protein-protein interactions and how these interactions affect the dynamic function of a key ligand-gated ion channel. (2) The functional significance of SAP97 interaction with GluR-A in layers 2/3. SAP97 is expressed in multipolar interneurons and our proposed experiments will specifically address the functional significance of GluR-A/SAP97 interaction to the dynamics of synaptic function. This work is basic research in the molecular basis of signaling in the brain. Defining basic principles of signaling provides a foundation for understanding the disruptions that can occur in disease states.
|Akgul, Gulcan; Wollmuth, Lonnie P (2010) Expression pattern of membrane-associated guanylate kinases in interneurons of the visual cortex. J Comp Neurol 518:4842-54|
|Traynelis, Stephen F; Wollmuth, Lonnie P; McBain, Chris J et al. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405-96|