Matthew Phillips - US grants

DESCRIPTION (provided by applicant): The central aim of the proposed research is to determine the coordinate systems the brain uses for representing the visual environment. In particular we investigate the coordinate system of the cortical map which represents salient objects and locations in the visual environment, and the coordinate system in which predictive remapping of neural activity from LIP takes place. This will advance the development of a monkey model of the human oculomotor system and thereby lay the foundation for future development of diagnostic, prognostic, and rehabilitative strategies for dealing with stroke and other pathologies which damage it. We use saccade adaptation to dissociate the location of a visual target which induces a saccade from the endpoint of the saccade which is made (Mclaughlin 1967), and measure neural activity with single-unit recordings. We run two different experiments in order to identify the two coordinate systems described above. In the first, we place the visual target in the receptive field of a neuron so that the endpoint of the monkey's adapted saccades fall outside the neuron's receptive field. LIP will exhibit neural activity in response to target onset and to the unadapted saccade (Colby et al. 1996). If neural activity persists through saccade adaptation, then the salience map uses visual coordinates;if not it uses motor coordinates. In the second experiment, we flash a peripheral stimulus around the time of a saccade, in the future receptive field of an LIP neuron. LIP neurons exhibit a post-saccadic response to this stimulus in the normal, unadapted situation, indicating predictive remapping of neural activity (Kusunoki &Goldberg 2003). If the post-saccadic response persists after adaptation, then predictive remapping is done in motor coordinates;if not it is tied to the visual stimulus. PUBLIC HEALTH RELEVANCE This project investigates the way the brain processes information about the visual world and how it updates with new information as the eyes move. Many pathologies, most prominently stroke, disable these brain functions. Since primates have very similar visual systems, understanding these functions in the monkey will facilitate the development of rehabilitative and therapeutic strategies in human patients.

PROJECT SUMMARY NMDA receptors (NMDARs) are neurotransmitter receptors found at nearly all vertebrate excitatory synapses and contribute to nearly all nervous system functions. Ca2+ influx through NMDARs regulates critical neuronal functions such as synaptic plasticity and the slow signaling kinetics of NMDARs greatly impact the integration of postsynaptic signals. Abnormal NMDAR activity is involved in a remarkable range of nervous system disorders including schizophrenia, major depressive disorder, stroke, neuropathic pain, and neurodegenerative diseases. Memantine (Mem) and ketamine (Ket) are two clinically useful NMDAR open channel blockers, antagonists that prevent ion flux by binding in and physically occluding the NMDAR channel. Despite their similar basic mechanisms of action and pharmacological properties, Mem and Ket display surprisingly disparate clinical effects. This proposal aims to investigate a major biophysical difference between how Mem and Ket affect NMDAR function that may contribute to the divergent effects of Mem and Ket on brain function. We recently discovered that inhibition of the GluN1/2A subtype of NMDAR by Mem, but not by Ket, depends on intracellular Ca2+ concentration ([Ca2+i]). Our data suggest that Ca2+i-dependent channel block (CDB) by Mem is due to Mem stabilizing a Ca2+-dependent desensitized state of the receptor, implying that Mem and Ket may differentially alter the timing of synaptic responses. Furthermore, Mem CDB appears to depend on NMDAR subtype, which varies by subcellular localization, developmental stage, and cell type. Thus, CDB may allow Mem to target different subpopulations of NMDARs than Ket and therefore could contribute greatly to the differential effects of Mem and Ket. However, the mechanisms underpinning Mem CDB are currently unknown, preventing further investigation of the role of CDB in the effects of Mem on brain function. The central goal of this proposal is to identify the mechanism and structural determinants underlying CDB by testing the hypothesis that Mem CDB results from the stabilization of a Ca2+-dependent desensitized receptor state by Mem. The long-term goals of this proposal are a) to better understand NMDAR-channel blocker interactions to identify features of beneficial drugs and b) to incorporate models of open channel blockers into models of neuronal circuit function. Electrophysiological recordings from cells modified to express a specific NMDAR subtype will be used to thoroughly characterize and identify the structural underpinnings of CDB. Data from these experiments will be incorporated into kinetic and molecular models of NMDAR-channel blocker interactions, which will then be validated and refined with additional experiments. This iterative combination of modeling and experimentation will aid our mechanistic understanding of how Mem inhibition is regulated by intracellular Ca2+. Findings from this proposal will have broad translational potential, aiding in the design of more clinically efficacious NMDAR antagonists, and will deepen our understanding of basic NMDAR function.