P01NS127769

Changes in the ionic basis of GABAergic inhibition that contribute to post-traumatic epilepsy - Brain injury is a common cause of medically intractable epilepsy. Because we do not understand the underlying pathophysiology, we can’t reduce the burden of medical intractability.

The overarching goal of this research program is to exploit a recently developed large animal gyrencephalic model of neocortical post-traumatic epilepsy (PTE) to elucidate a mechanism of neocortical epileptogenesis: chronic compromise of the ionic basis for GABA-mediated inhibition. Disinhibition is a fundamental element of ictogenesis, but thus far we have not found the mechanism of disinhibition in chronic epilepsy.

There are two salient clues: first, anticonvulsants that increase GABA conductance often do not ameliorate PTE; and second, studies in human intractable epilepsy have found a positive, disinhibitory shift in the reversal potential for GABAA receptor-mediated membrane currents (EGABA).

Here we will test the hypothesis that glial reconstruction of the brain’s extracellular matrix after injury results in increased displacement of extracellular chloride (Cl-O) by the sulfate moieties of the proteoglycans that comprise the new matrix. To test this hypothesis, we will employ a large-animal PTE model in which local epileptogenesis occurs after well-characterized neocortical injury (Project 1 and Large Animal Core).

This localization of epileptogenesis is critical for correlation of changes in Cl-O, network structure, and epilepsy. In this injured neocortical area, we will use longitudinal 2-photon in vivo calcium imaging to test for the network changes expected from disinhibition (Project 2 and Microscopy Core).

In the injured neocortical area, we will use 2-photon fluorescence lifetime imaging (FLIM) and newly-synthesized Cl- indicators to test for changes in the local Cl-O and intracellular chloride (Cl-I) that would drive disinhibition by depolarizing EGABA and reducing the efficacy of shunting inhibition (Project 3).

The 3 projects have a common third aim: to correlate epileptogenesis (Project 1) with network disinhibition (Project 2) that are associated with chronic changes in Cl-O and Cl-I (Project 3). Together, these projects and cores will test a novel mechanism of epileptogenesis and medical intractability that could be ameliorated by short-term inhibition of the disassembly of the brain’s extracellular matrix at the time of injury using MMP inhibitors whose efficacy will be screened in Project 3, Aim 2.

The General Hospital Corporation

(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 NEUROSCIENCE WORKFORCE DEVELOPMENT, 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]

Charlestown, Massachusetts 02129 United States

Single Zip Code

NINDS Program Project Grant (P01 Clinical Trial Optional) (PAR-21-181)

Amendment Since initial award the total obligations have increased 185% from $1,379,528 to $3,929,901.