LOCAL INTERACTIONS BETWEEN HIPPOCAMPAL NEURONS

Summary

Principal Investigator: F Dudek
Abstract: Many studies have analyzed axonal sprouting and synaptic reorganization of local excitatory circuits in animal models of temporal lobe epilepsy, but relatively little electrophysiological research at the single-neuron level has been conducted on reorganization of local inhibitory circuits during epileptogenesis. Furthermore, the dynamic properties of these reorganized circuits during repetitive synaptic activation, as expected during the onset of hippocampal seizures, are relatively unknown The general questions to be addressed in the proposed experiments are what are the short- and long-term alterations in local inhibitory circuits after status epilepticus, and does synaptic depression during repetitive activation of these circuits contribute to seizure propagation during chronic epileptogenesis? The proposed experiments will use hippocampal slices from rats with kainate-induced epilepsy to determine how loss of synaptic input and subsequent synaptic reorganization after status epilepticus leads to changes in local inhibitory circuits in the dentate gyrus and the CA1 area Inhibitory circuits in these two hippocampal areas appear to be different after SE The experiments will address the following specific questions (1) Does axonal sprouting of principal neurons in the hippocampus (e g, dentate granule cells and CA1 pyramidal cells) lead to formation of functional excitatory synapses on inhibitory interneurons? (2) Do interneurons sprout axon collaterals, and form new inhibitory synapses with principal neurons? (3) How does repetitive activation of local inhibitory circuits alter transmission through this network, and are these areas of the hippocampus abnormally sensitive to repetitive activation at periods after status epilepticus when recurrent spontaneous seizures occur? Aim 3 will utilize frequencies of repetitive stimulation that simulate the patterns of synaptic activation observed at the onset of chronically recorded electrographic seizures in rats with kainate-induced epilepsy These experiments aim to provide increased understanding about the reorganization of inhibitory circuits that may contribute to temporal lobe epilepsy, and how activity-dependent depression of local inhibitory circuits may promote the spread of epileptic seizures The systems to be investigated are prime targets for therapeutic intervention to prevent seizures in people with intractable temporal lobe epilepsy.
Funding Period: 1987-12-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc Repetitive perforant-path stimulation induces epileptiform bursts in minislices of dentate gyrus from rats with kainate-induced epilepsy
    Li Rong Shao
    Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
    J Neurophysiol 105:522-7. 2011
  2. pmc Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system
    J E Rash
    Department of Biomedical Sciences, Program in Neuronal Growth and Development, and Program in Cell and Molecular Biology, Campus Delivery 1617, Colorado State University, Fort Collins, CO 80523, USA
    Neuroscience 168:982-1008. 2010
  3. pmc Single and repetitive paired-pulse suppression: a parametric analysis and assessment of usefulness in epilepsy research
    SIMON WALDBAUM
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, Colorado, USA
    Epilepsia 50:904-16. 2009
  4. ncbi Epilepsy and reproductive disorders: the role of the gonadotropin-releasing hormone network
    Jessica A Fawley
    Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
    Epilepsy Behav 8:477-82. 2006
  5. pmc A chronic histopathological and electrophysiological analysis of a rodent hypoxic-ischemic brain injury model and its use as a model of epilepsy
    P A Williams
    Department of Biomedical Sciences, Neurobiology Section, Colorado State University, Fort Collins, CO 80523, USA
    Neuroscience 149:943-61. 2007
  6. ncbi Neuropathogical features of a rat model for perinatal hypoxic-ischemic encephalopathy with associated epilepsy
    Shilpa D Kadam
    Department of Biomedical Sciences, Neurosciences Division, Colorado State University, Fort Collins, Colorado 80523, USA
    J Comp Neurol 505:716-37. 2007
  7. ncbi Changes in mIPSCs and sIPSCs after kainate treatment: evidence for loss of inhibitory input to dentate granule cells and possible compensatory responses
    Li Rong Shao
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, CO 80523, USA
    J Neurophysiol 94:952-60. 2005
  8. ncbi Commentary: a skeptical view of experimental gene therapy to block epileptogenesis
    F Edward Dudek
    Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA
    Neurotherapeutics 6:319-22. 2009
  9. ncbi Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy
    Heidi L Grabenstatter
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, Colorado 80523, USA
    Epilepsia 46:8-14. 2005
  10. pmc Both synaptic and intrinsic mechanisms underlie the different properties of population bursts in the hippocampal CA3 area of immature versus adult rats
    Li Rong Shao
    Department of Biomedical Sciences, Anatomy and Neurobiology, Colorado State University, Fort Collins, CO 80523, USA
    J Physiol 587:5907-23. 2009

Scientific Experts

  • JOHN RASH
  • Jessica A Fawley
  • F Dudek
  • Li Rong Shao
  • Shilpa D Kadam
  • SIMON WALDBAUM
  • P A Williams
  • Heidi L Grabenstatter
  • Kevin J Staley
  • Andrew M White
  • Phillip L Chapman
  • Philip A Williams
  • Damien J Ferraro

Detail Information

Publications12

  1. pmc Repetitive perforant-path stimulation induces epileptiform bursts in minislices of dentate gyrus from rats with kainate-induced epilepsy
    Li Rong Shao
    Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
    J Neurophysiol 105:522-7. 2011
    ..e., 5-10 hz)...
  2. pmc Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system
    J E Rash
    Department of Biomedical Sciences, Program in Neuronal Growth and Development, and Program in Cell and Molecular Biology, Campus Delivery 1617, Colorado State University, Fort Collins, CO 80523, USA
    Neuroscience 168:982-1008. 2010
    ..Continued progress in molecular identification and subcellular mapping of glial ion and water channels will lead to a better understanding of demyelinating diseases of the CNS and to development of improved treatment regimens...
  3. pmc Single and repetitive paired-pulse suppression: a parametric analysis and assessment of usefulness in epilepsy research
    SIMON WALDBAUM
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, Colorado, USA
    Epilepsia 50:904-16. 2009
    ....
  4. ncbi Epilepsy and reproductive disorders: the role of the gonadotropin-releasing hormone network
    Jessica A Fawley
    Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
    Epilepsy Behav 8:477-82. 2006
    ..This review provides a brief overview of evidence from experimental animal and clinical studies exploring the basis for epilepsy-associated reproductive abnormalities...
  5. pmc A chronic histopathological and electrophysiological analysis of a rodent hypoxic-ischemic brain injury model and its use as a model of epilepsy
    P A Williams
    Department of Biomedical Sciences, Neurobiology Section, Colorado State University, Fort Collins, CO 80523, USA
    Neuroscience 149:943-61. 2007
    ....
  6. ncbi Neuropathogical features of a rat model for perinatal hypoxic-ischemic encephalopathy with associated epilepsy
    Shilpa D Kadam
    Department of Biomedical Sciences, Neurosciences Division, Colorado State University, Fort Collins, Colorado 80523, USA
    J Comp Neurol 505:716-37. 2007
    ..The occurrence of cortical abnormalities that are associated with epilepsy in humans correlates with the consequent detection of spontaneous recurrent seizures...
  7. ncbi Changes in mIPSCs and sIPSCs after kainate treatment: evidence for loss of inhibitory input to dentate granule cells and possible compensatory responses
    Li Rong Shao
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, CO 80523, USA
    J Neurophysiol 94:952-60. 2005
    ....
  8. ncbi Commentary: a skeptical view of experimental gene therapy to block epileptogenesis
    F Edward Dudek
    Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA
    Neurotherapeutics 6:319-22. 2009
    ....
  9. ncbi Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy
    Heidi L Grabenstatter
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, Colorado 80523, USA
    Epilepsia 46:8-14. 2005
    ..As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol...
  10. pmc Both synaptic and intrinsic mechanisms underlie the different properties of population bursts in the hippocampal CA3 area of immature versus adult rats
    Li Rong Shao
    Department of Biomedical Sciences, Anatomy and Neurobiology, Colorado State University, Fort Collins, CO 80523, USA
    J Physiol 587:5907-23. 2009
    ....
  11. pmc Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy
    Shilpa D Kadam
    Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA
    J Neurosci 30:404-15. 2010
    ..Thus, prolonged, continuous seizure monitoring directly demonstrated that the acquired epilepsy after perinatal HI was progressive with seizure clusters and was consistently associated with a cerebral infarct...
  12. ncbi Electrophysiological evidence using focal flash photolysis of caged glutamate that CA1 pyramidal cells receive excitatory synaptic input from the subiculum
    Li Rong Shao
    Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, CO 80523, USA
    J Neurophysiol 93:3007-11. 2005
    ..Thus a reciprocal excitatory synaptic circuit connects the subiculum and the CA1 area in the normal adult rat...