R37NS036715

THE DYNAMIC AMPA RECEPTOR INTERACTOME DURING PLASTICITY AND LEARNING - SUMMARY AMPA RECEPTORS (AMPARS) ARE THE MAJOR EXCITATORY NEUROTRANSMITTER RECEPTORS IN THE BRAIN AND THEIR DYNAMIC TRAFFICKING IS ESSENTIAL FOR SYNAPTIC PLASTICITY THAT UNDERLIES MEMORY. AMPARS PARTICIPATE IN VAST POSTSYNAPTIC PROTEIN COMPLEXES THAT IMPACT THEIR PROPERTIES AND TRAFFICKING. WE HYPOTHESIZE THAT DYNAMIC REARRANGEMENTS IN POSTSYNAPTIC PROTEIN-PROTEIN INTERACTIONS (PPIS) TUNE AMPAR LEVELS IN RESPONSE TO STIMULI, GIVING RISE TO SYNAPTIC PLASTICITY AND MEMORY. WE PREVIOUSLY IDENTIFIED GRIP1/GRIP2, PICK1 AND OTHERS AS KEY SYNAPTIC PROTEINS THAT REGULATE AMPAR TRAFFICKING AND PLASTICITY THROUGH DYNAMIC AND SELECTIVE INTERACTIONS WITH THE CYTOPLASMIC DOMAINS OF THE RECEPTOR. RECENT EVIDENCE SUGGESTS THAT AMPARS MIGHT ALSO REGULATED BY YET UNIDENTIFIED INTERACTIONS WITH THEIR EXTRACELLULAR N-TERMINAL DOMAIN. ADVANCES IN PROXIMITY-DEPENDENT BIOTINYLATION WITH MINITURBO HAS RECENTLY ENABLED IDENTIFICATION OF IN VIVO PROTEIN INTERACTIONS, OCCURRING BOTH EXTRACELLULARLY AND INTRACELLULARLY, BY QUANTITATIVE MASS SPECTROMETRY. THIS TECHNOLOGY HAS BEEN PIONEERED TO MAP SYNAPSE COMPOSITION IN VIVO, BUT HAS NEVER BEEN USED TO STUDY PPIS OR SYNAPTIC PLASTICITY IN THIS CAPACITY. WE WILL EXTEND OUR CHARACTERIZATION OF AMPAR TRAFFICKING DURING PLASTICITY IN VIVO BY FUSING THE GENETICALLY ENCODABLE BIOTIN LIGASE, MINITURBO, TO EITHER THE EXTRACELLULAR N- OR INTRACELLULAR C-TERMINI OF GLUA1/2-AMPARS AND DELIVER THEM TO THE HIPPOCAMPUS OF MICE USING VIRUSES. WE WILL THEN OBSERVE HOW AMPAR PPIS CHANGE IN TWO COMPLEMENTARY MODELS OF PLASTICITY – THE INHIBITORY AVOIDANCE MODEL OF RODENT MEMORY AND ITS DIRECT ELECTROPHYSIOLOGICAL CORRELATE, LTP OF THE CA3CA1 SYNAPSE. IDENTIFICATION OF PPIS THAT ARE COMMON TO THESE TWO MODELS OF PLASTICITY WILL NOT ONLY FURTHER OUR MODEL OF AMPAR TRAFFICKING DURING PLASTICITY BUT WILL ALSO IDENTIFY COMMON BIOCHEMICAL PROCESSES BETWEEN LTP AND LEARNING AND MEMORY. MOREOVER, SYNAPTIC PROTEINS THAT IMPACT AMPAR TRAFFICKING HAVE RECENTLY BEEN ASSOCIATED WITH VARIOUS NEUROPSYCHIATRIC DISORDERS SUCH AS INTELLECTUAL DISABILITY, AUTISM, AND SCHIZOPHRENIA AND THUS UNDERSTANDING THESE PROCESSES MAY HAVE IMPACT ON POTENTIAL THERAPEUTIC APPROACHES TO THESE DISORDERS.

The Johns Hopkins University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM; RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS; RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS; IMPROVED METHODS OF DISEASE PREVENTION; NEW METHODS OF DIAGNOSIS AND TREATMENT; DRUG DEVELOPMENT; DEVELOPMENT OF NEURAL DEVICES; CLINICAL TRIALS; AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH; SYNAPSE FORMATION, FUNCTION, AND PLASTICITY; LEARNING AND MEMORY; CHANNELS, TRANSPORTERS, AND PUMPS; CIRCUIT FORMATION AND MODULATION; BEHAVIORAL AND COGNITIVE NEUROSCIENCE; SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION; NEUROENDOCRINE SYSTEMS; SLEEP AND CIRCADIAN RHYTHMS; AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE; TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM; NEURODEGENERATIVE DISORDERS; MOVEMENT DISORDERS; BRAIN TUMORS; CONVULSIVE DISORDERS; INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM; IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS; DISORDERS RELATED TO SLEEP; AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE THE NEUROSCIENCE WORKFORCE, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM; TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Baltimore, Maryland 212051832 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 02/28/26 to 02/28/29 and the total obligations have increased 402% from $644,481 to $3,235,152.