Effects of TrkB Activation on Abnormalities in Neocortical FS Interneurons

Summary

Principal Investigator: DAVID ALLAN PRINCE
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-04-01 - 2018-03-31
more information: NIH RePORT

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  2. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
  3. MODULATION OF NEOCORTICAL INTERNEURONAL FUNCTION
    DAVID ALLAN PRINCE; Fiscal Year: 2013
  4. Role of Thalamus in Post-stroke epileptogenesis
    Jeanne T Paz; Fiscal Year: 2013
  5. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  6. Alzheimer's Disease Research Center
    Oscar L Lopez; Fiscal Year: 2013
  7. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
  8. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
  9. Neurocircuitry Underlying DBS Effects in OCD: A Window Into Mechanisms of Action
    Suzanne N Haber; Fiscal Year: 2013

Detail Information

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  2. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  3. MODULATION OF NEOCORTICAL INTERNEURONAL FUNCTION
    DAVID ALLAN PRINCE; Fiscal Year: 2013
    ..The long term goals are to identify critical abnormalities that might eventually be targets for selective agents that would used to prevent or treat human posttraumatic epilepsy. ..
  4. Role of Thalamus in Post-stroke epileptogenesis
    Jeanne T Paz; Fiscal Year: 2013
    ..My long- term goal is to continue studying the mechanisms generating abnormal neural network oscillations associated with neurological disorders such as epilepsy or Parkinson's disease in an independent academic setting. ..
  5. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  6. Alzheimer's Disease Research Center
    Oscar L Lopez; Fiscal Year: 2013
    ..Alzheimer's centers such as the one in Pittsburgh play a critical role in the nation's struggle to: 1) care for those currently afflicted;2) improve diagnosis and treatment;and 3) find a means of prevention. ..
  7. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  8. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  9. Neurocircuitry Underlying DBS Effects in OCD: A Window Into Mechanisms of Action
    Suzanne N Haber; Fiscal Year: 2013
    ..Results from these studies will also make important new contributions to our understanding of the basic mechanisms of DBS. ..