Traumatic brain injury (TBI) results in abnormalities in cerebral cortex and disorders of sensory and motor function, cognitive abnormalities and epilepsy. The potential development of epilepsy by the large number of individuals, who have survived severe concussive injury during recent conflicts, emphasizes the need for understanding the underlying pathophysiological processes and the development of prophylactic strategies (Garga and Lowenstein, 2006). A goal of this project is to obtain basic information on approaches that may improve or prevent such posttraumatic abnormalities. Injury to nerve cells that release the chemical transmitter GABA is a common result of TBI. Improvement in the structure and function of these inhibitory cells, """"""""interneurons"""""""", may prevent some of the consequences of injury, including epilepsy. Preliminary results show that fast-spiking (FS) inhibitory interneurons, the most common type of interneuron in cortex, have abnormal nerve processes and defects in releasing GABA in areas of cortical injury produced by partially cutting connections with surrounding brain (""""""""undercuts""""""""). Undercut cortex becomes hyperexcitable due to this and other defects and often generates epileptiform electrical activity that resembles EEG activity in human focal epilepsy. A neurotrophic protein BDNF, and its receptor TrkB, are important for development, growth and maintenance of interneurons, and are reduced in the injured area, leading to the hypothesis that TrkB activation may correct abnormalities in FS or other interneurons and improve function in the injured cortex. To test this hypothesis, undercuts will be made in anesthetized rodents, and animals treated with a newly- engineered """"""""small"""""""" molecule, LM22A-4, that enters the brain and activates the TrkB receptor. After treatment for ~2 weeks, rodents are re-anesthetized, and standard in vitro slice and patch clamp techniques used to obtain recordings from single interneurons and excitatory cells in areas of injury from drug-treated animals and saline controls. Activities of individual nerve cells and large groups of neurons (""""""""field potentials"""""""") will be analyzed with appropriate software. Laser-activated release of the excitatory chemical transmitter, glutamate, will be used to map changes in excitatory and inhibitory connections in neural networks within individual slices, and effects of chronic LM22A-4 treatment. The structure of single cells will be measured after filling them with a marker called biocytin, staining slices with antibodies, and using computer-controlled microscopic imaging techniques, including light and confocal microscopy.
The aims of these experiments are to determine whether activation of the TrkB receptor will improve the anatomical and functional abnormalities in FS interneurons, restore normal release of GABA and favorably affect nerve circuits in the injured cortex.

Public Health Relevance

Traumatic brain injury (TBI) and its consequences, such as epilepsy and other abnormalities, are major public health problems for both military personnel and civilians in the U.S. and world-wide. Trauma often injures inhibitory nerve cells that are important in controlling excessive brain activity and regulating normal brain functions. In these experiments, a newly-developed molecule that acts on an important brain receptor protein will be used to rehabilitate these injured inhibitory cells, and restore their normal structure and activities, an approach that may lead to new treatments to prevent posttraumatic epilepsy and other consequences of brain trauma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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Stanford University
Schools of Medicine
United States
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Takahashi, D Koji; Gu, Feng; Parada, Isabel et al. (2016) Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma. Neurobiol Dis 91:166-81