Abnormalities in Fast - Spiking Interneurons of Chronically Epileptogenic Cortex

Summary

Principal Investigator: DAVID ALLAN PRINCE
Abstract: Penetrating Injuries of the brain are a frequent cause of epilepsy in man, making it important to understand the underlying pathogenetic mechanisms. Loss of inhibition has been found in a number of models of epilepsy and may be important in posttraumatic human seizure disorders. The specific aims of the proposed experiments focus on two types of abnormality, found in a group of inhibitory cells within the partial cortical isolation model of posttraumatic epilepsy. These fast-spiking (FS) interneurons have a major influence on the control of runaway activity in the cortex which, if unchecked, can lead to epileptic seizures. Anatomical changes in the axons of FS cells suggest that they make fewer functional contacts that would release GABA on themselves via "autaptic1 synapses, and on excitatory pyramidal cells. They also have reductions in a vital enzyme, the sodium pump. In vitro slices from chronically injured epileptogenic cortex together with patch clamp techniques and dual recordings will be used to assess the functional disorders in inhibition that occur as a result of these axonal abnormalities. The long term goal of such experiments is to uncover links between injury and the appearance of epilepsy that can be modified by strategies for prevention or treatment, such as development of targeted drugs. For example, if reductions in the "sodium pump" contribute to cortical hyperexcitability and epileptogenesis, if may be possible to use pharmacological agents or neurotransmitters to boost pump activity and ameliorate seizure activity. The discovery that important cortical inhibitory neurons are "disconnected" from their targets after injury, rather than being killed, may open the way for approaches that will promote "rewiring" of these connections to restore the balance between excitatory and inhibitory processes in the damaged areas.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. ncbi Barrel cortex microcircuits: thalamocortical feedforward inhibition in spiny stellate cells is mediated by a small number of fast-spiking interneurons
    Qian Quan Sun
    Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, California 94305, USA
    J Neurosci 26:1219-30. 2006
  2. pmc Presynaptic inhibitory terminals are functionally abnormal in a rat model of posttraumatic epilepsy
    Leonardo C Faria
    Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, California 94305 5122, USA
    J Neurophysiol 104:280-90. 2010
  3. pmc Differential effects of Na+-K+ ATPase blockade on cortical layer V neurons
    Trent R Anderson
    Neurology and Neurological Sciences, Stanford University, CA 94305, USA
    J Physiol 588:4401-14. 2010
  4. pmc Reorganization of inhibitory synaptic circuits in rodent chronically injured epileptogenic neocortex
    Xiaoming Jin
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cereb Cortex 21:1094-104. 2011
  5. pmc Astrocytes as gatekeepers of GABAB receptor function
    Mark P Beenhakker
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 30:15262-76. 2010
  6. pmc Targets for preventing epilepsy following cortical injury
    Huifang Li
    Epilepsy Research Laboratory, Department of Neurology and Neurological Sciences, Stanford University Sch of Medicine, 300 Pasteur Dr, Stanford, CA 94305, United States
    Neurosci Lett 497:172-6. 2011
  7. pmc Understanding the physical mechanism of transition to epileptic seizures
    Dorian Aur
    Dept of Comparative Medicine, Stanford University, Palo Alto, CA, United States
    J Neurosci Methods 200:80-5. 2011
  8. pmc Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 32:1183-96. 2012
  9. pmc Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, CA 94305, United States
    Epilepsy Res 102:153-9. 2012
  10. pmc Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma
    Huifang Li
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
    Neurobiol Dis 48:429-38. 2012

Scientific Experts

  • DAVID ALLAN contact PRINCE
  • John R Huguenard
  • Julia Brill
  • Isabel Parada
  • Xiaoming Jin
  • Hiroaki Tani
  • Huifang Li
  • Paul S Buckmaster
  • Leonardo C Faria
  • Wei Zhang
  • Yunyong Ma
  • Mark P Beenhakker
  • C G Dulla
  • Story C Landis
  • MATTHEW E CARTER
  • Whitney McDonald
  • Dorian Aur
  • Christine K Lee
  • Trent R Anderson
  • Jeanne T Paz
  • Yunxiang Chu
  • Astra S Bryant
  • Y Chu
  • Richard J Reimer
  • Chris Dulla
  • Qian Quan Sun
  • Brian Halabisky
  • J R Huguenard
  • J Brill
  • H Tani
  • R J Reimer
  • Robert J Ferrante
  • Marc Fisher
  • Robert B Darnell
  • Ellis Unger
  • Richard T Moxley
  • Megan M Haney
  • John D Porter
  • Kalyani Narasimhan
  • Robert A Gross
  • Sharon E Hesterlee
  • Chris P Austin
  • Eileen W Bradley
  • Robert Finkelstein
  • John Huguenard
  • Ronald G Crystal
  • Howard E Gendelman
  • Amelie K Gubitz
  • Linda J Noble
  • Ursula Utz
  • Katrina Kelner
  • David W Howells
  • Michael S Levine
  • Ben A Barres
  • Luis de Lecea
  • Steve Perrin
  • Robi Blumenstein
  • Khusru Asadullah
  • Dimitri Krainc
  • John M McCall
  • Kevin D Graber
  • Walter Koroshetz
  • John L Goudreau
  • Howard Fillit
  • Stanley E Lazic
  • Robert M Golub
  • Shai D Silberberg
  • Patricia Bonnavion
  • Ramon Huerta
  • Susan G Amara
  • Malcolm R Macleod
  • Sha Jin
  • Oswald Steward
  • Leonardo Faria
  • D Koji Takahashi
  • Kevin Graber
  • Beth Stevens
  • Catherine A Christian
  • Ben Barres
  • Alexei Pesic
  • Chris G Dulla
  • Bojia Li
  • I Parada
  • Rich J Reimer
  • Sakiko Okumoto
  • Wolf B Frommer
  • Michelle Wynn
  • Anita E Bandrowski
  • Fran Shen

Detail Information

Publications32

  1. ncbi Barrel cortex microcircuits: thalamocortical feedforward inhibition in spiny stellate cells is mediated by a small number of fast-spiking interneurons
    Qian Quan Sun
    Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, California 94305, USA
    J Neurosci 26:1219-30. 2006
    ..The ready activation of FS cells by TC inputs, coupled with powerful feedforward inhibition from these neurons, would profoundly influence sensory processing and constrain runaway excitation in vivo...
  2. pmc Presynaptic inhibitory terminals are functionally abnormal in a rat model of posttraumatic epilepsy
    Leonardo C Faria
    Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, California 94305 5122, USA
    J Neurophysiol 104:280-90. 2010
    ..Blockade of GABA(B) receptors did not affect the paired results. These findings suggest that there are functional alterations in GABAergic presynaptic terminals onto both Pyr and FS cells in this model of posttraumatic epileptogenesis...
  3. pmc Differential effects of Na+-K+ ATPase blockade on cortical layer V neurons
    Trent R Anderson
    Neurology and Neurological Sciences, Stanford University, CA 94305, USA
    J Physiol 588:4401-14. 2010
    ..These differences may have important consequences in pathophysiological disorders associated with down-regulation of Na(+)-K(+) ATPase and hyperexcitability within cortical networks...
  4. pmc Reorganization of inhibitory synaptic circuits in rodent chronically injured epileptogenic neocortex
    Xiaoming Jin
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cereb Cortex 21:1094-104. 2011
    ....
  5. pmc Astrocytes as gatekeepers of GABAB receptor function
    Mark P Beenhakker
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 30:15262-76. 2010
    ..Targeting this gatekeeper function may provide new pharmacotherapeutic opportunities to prevent the excessive GABA(B) receptor activation that appears necessary for thalamic seizure generation...
  6. pmc Targets for preventing epilepsy following cortical injury
    Huifang Li
    Epilepsy Research Laboratory, Department of Neurology and Neurological Sciences, Stanford University Sch of Medicine, 300 Pasteur Dr, Stanford, CA 94305, United States
    Neurosci Lett 497:172-6. 2011
    ..However, a number of key issues must be addressed before these results can be used to frame clinical antiepileptogenic therapy...
  7. pmc Understanding the physical mechanism of transition to epileptic seizures
    Dorian Aur
    Dept of Comparative Medicine, Stanford University, Palo Alto, CA, United States
    J Neurosci Methods 200:80-5. 2011
    ..The alteration in neuronal regulation and the nature of physical phenomena involved in this transition supports some models of seizure generation and rules out others...
  8. pmc Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 32:1183-96. 2012
    ..The aberrant development of these additional positive-feedback circuits might contribute to epileptogenesis in temporal lobe epilepsy...
  9. pmc Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, CA 94305, United States
    Epilepsy Res 102:153-9. 2012
    ..Those results are substantially better than that of the total sample in which 31% failed to develop status epilepticus and only 34% developed status epilepticus and survived...
  10. pmc Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma
    Huifang Li
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
    Neurobiol Dis 48:429-38. 2012
    ..The findings may suggest the potential use of GBP as an antiepileptogenic agent following traumatic brain injury...
  11. pmc Mechanism for Hypocretin-mediated sleep-to-wake transitions
    MATTHEW E CARTER
    Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 109:E2635-44. 2012
    ..This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain...
  12. ncbi Glutamate biosensor imaging reveals dysregulation of glutamatergic pathways in a model of developmental cortical malformation
    C G Dulla
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA Electronic address
    Neurobiol Dis 49:232-46. 2013
    ....
  13. pmc A call for transparent reporting to optimize the predictive value of preclinical research
    Story C Landis
    National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892, USA
    Nature 490:187-91. 2012
    ..Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress...
  14. pmc Enhanced synaptic connectivity and epilepsy in C1q knockout mice
    Yunxiang Chu
    Department of Neurology and Neurological Sciences and Neurobiology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 107:7975-80. 2010
    ..Results indicate that epileptogenesis in C1q KO mice is related to a genetically determined failure to prune excessive excitatory synapses during development...
  15. pmc Enhanced infragranular and supragranular synaptic input onto layer 5 pyramidal neurons in a rat model of cortical dysplasia
    Julia Brill
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA
    Cereb Cortex 20:2926-38. 2010
    ..These increases in both excitatory and inhibitory connectivity may limit the extent of circuit hyperexcitability...
  16. ncbi Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epileptogenic neocortex in rats
    Xiaoming Jin
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 26:4891-900. 2006
    ..These changes may shift the balance within cortical circuits toward increased synaptic excitation and contribute to epileptogenesis...
  17. ncbi Electrophysiological classification of somatostatin-positive interneurons in mouse sensorimotor cortex
    Brian Halabisky
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 5122, USA
    J Neurophysiol 96:834-45. 2006
    ..Our data are consistent with a heterogeneous population of neurons based on electrophysiological properties and indicate that EGFP expression in the GIN mouse is not restricted to a single class of somatostatin-positive interneuron...
  18. pmc Modulation of epileptiform activity by glutamine and system A transport in a model of post-traumatic epilepsy
    Hiroaki Tani
    Department of Neurology, Stanford University Medical Center, Stanford, CA 94305, USA
    Neurobiol Dis 25:230-8. 2007
    ....
  19. pmc Imaging of glutamate in brain slices using FRET sensors
    Chris Dulla
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Room M016, Stanford, CA 94305 5122, USA
    J Neurosci Methods 168:306-19. 2008
    ..This technique also provides a unique assay of network activity that compliments alternative techniques such as voltage-sensitive dyes and multi-electrode arrays...
  20. pmc Sequential changes in AMPA receptor targeting in the developing neocortical excitatory circuit
    Julia Brill
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 28:13918-28. 2008
    ....
  21. pmc Robust short-latency perisomatic inhibition onto neocortical pyramidal cells detected by laser-scanning photostimulation
    Julia Brill
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 29:7413-23. 2009
    ..Because of their magnitude, progressive recruitment, and short latency, slIPSCs are a effective mechanism of regulating excitability in neocortical circuits...
  22. pmc Maintenance of thalamic epileptiform activity depends on the astrocytic glutamate-glutamine cycle
    Astra S Bryant
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305 5122, USA
    J Neurophysiol 102:2880-8. 2009
    ....
  23. pmc Martinotti cells: community organizers
    Christine K Lee
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
    Neuron 69:1042-5. 2011
    ....
  24. pmc Focal cortical infarcts alter intrinsic excitability and synaptic excitation in the reticular thalamic nucleus
    Jeanne T Paz
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 30:5465-79. 2010
    ..In addition, such changes could be maladaptive, leading to injury-induced epilepsy...
  25. pmc Glutamine is required for persistent epileptiform activity in the disinhibited neocortical brain slice
    Hiroaki Tani
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    J Neurosci 30:1288-300. 2010
    ..These results indicate that availability of glutamine influences neuronal release of glutamate during periods of intense network activity...
  26. pmc Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 29:7846-56. 2009
    ..These findings suggest dysfunction of the dentate basket cell circuit could contribute to hyperexcitability and seizures...
  27. pmc Functional alterations in GABAergic fast-spiking interneurons in chronically injured epileptogenic neocortex
    Yunyong Ma
    Dept of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 5122, USA
    Neurobiol Dis 47:102-13. 2012
    ..Given the marked reduction in synaptic strength, other defects in the presynaptic vesicle release machinery likely occur, as well...
  28. pmc Epilepsy following cortical injury: cellular and molecular mechanisms as targets for potential prophylaxis
    David A Prince
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    Epilepsia 50:30-40. 2009
    ..However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved...
  29. pmc Temporal and topographic alterations in expression of the alpha3 isoform of Na+, K(+)-ATPase in the rat freeze lesion model of microgyria and epileptogenesis
    Y Chu
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, M016, Stanford University, Stanford, CA 94305, USA
    Neuroscience 162:339-48. 2009
    ..The significant decreases in Na(+),K(+)-ATPase in the paramicrogyral cortex may contribute to epileptogenesis...
  30. pmc Interneuronal calcium channel abnormalities in posttraumatic epileptogenic neocortex
    Leonardo C Faria
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
    Neurobiol Dis 45:821-8. 2012
    ..We suggest that decreased calcium influx via N-type channels in presynaptic GABAergic terminals is a mechanism contributing to decreased inhibitory input onto layer V Pyr cells in this model of cortical posttraumatic epileptogenesis...