Presynaptic mechanisms controlling excitatory and inhibitory synaptic transmission in the cerebral cortex have critical roles in normal information processing and also may contribute to the pathophysiology of a variety of brain disorders such as cognitive decline and epilepsy. The proposed experiments focus primarily on inhibitory synaptic transmission mediated by gamma amino butyric acid (GABA)-containing fast-spiking (FS) inhibitory interneurons and its modulation by activities of sodium-potassium ATPase (NKA, the sodium pump). FS interneurons mediate the most common and strongest form of inhibition and are known to be vulnerable to injury. Preliminary data show that immunoreactivity for ?3KA, the main pump isoform in interneurons, is decreased in axonal terminals of FS cells in partially isolated (undercut or UC) neocortex. We will test the hypothesis that FS to excitatory cell GABAergic transmission will be compromised by decreases in ?3KA activity, whether it occurs in partially isolated epileptogenic cortex, via treatment with cardiotonic steroids, or in epileptic mice with genetically altered NKA alpha3 subunit.
Specific aims are to 1) assess effects of cardiotonic steroids or cortical injury on pump current and the dynamics of FS to excitatory cell inhibition;2) study functional effects of enhancing ?3KA expression in injured or Myshkin mouse cortex with a small molecule partial TrkB agonist;and 3) test the hypothesis that properties of FS GABAergic neurons and transmission from FS cells will be selectively altered in Myshkin mice with a genetically induced epilepsy due to mutations in the ?3 pump subunit. Techniques will include paired recordings in cortical slices to obtain unitary (u) inhibitry postsynaptic currents (IPSCs) generated selectively by FS cells;optogenetic approaches in parvalbumin/ChR2 mice to selectively activate FS cells;and both laser scanning photostimulation and multiple simultaneous extracellular recordings to monitor effects network effects. The partial cortical isolation model will be used to provide chronically injured, epileptogenic slices and assess changes in pump function that might contribute to hyperexcitability. The goals are to identify pump activities that influence GABAergic transmission, abnormalities induced by injury or genetic alterations in pump function that may contribute to hyperexcitability and epileptogenesis;and test whether enhancing NKA expression will rescue compromised FS cell-mediated inhibition in the UC cortex.

Public Health Relevance

Epilepsy following brain injury is a major health problem and the mechanisms that lead from injury to epilepsy in man are poorly understood. The proposed experiments will focus on a model of local brain trauma and on genetic epilepsy in rodents to better understand the involvement of a key protein, called sodium/potassium ATPase, in regulating inhibition in normal and injured brain. Experiments designed to enhance the activities of this important molecule after brain injury may yield information that will improve approaches for improving brain function and preventing posttraumatic epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Gu, Feng; Parada, Isabel; Shen, Fran et al. (2017) Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis. Neurobiol Dis 108:100-114
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
Prince, David A (2014) How do we make models that are useful in understanding partial epilepsies? Adv Exp Med Biol 813:233-41
Jin, Xiaoming; Jiang, Kewen; Prince, David A (2014) Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria. J Neurophysiol 112:1703-13
Mantoan Ritter, Laura; Golshani, Peyman; Takahashi, Koji et al. (2014) WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55:1693-702
Mao, Rong; Schummers, James; Knoblich, Ulf et al. (2012) Influence of a subtype of inhibitory interneuron on stimulus-specific responses in visual cortex. Cereb Cortex 22:493-508
Ma, Yunyong; Prince, David A (2012) Functional alterations in GABAergic fast-spiking interneurons in chronically injured epileptogenic neocortex. Neurobiol Dis 47:102-13
Faria, Leonardo C; Parada, Isabel; Prince, David A (2012) Interneuronal calcium channel abnormalities in posttraumatic epileptogenic neocortex. Neurobiol Dis 45:821-8
Li, Huifang; McDonald, Whitney; Parada, Isabel et al. (2011) Targets for preventing epilepsy following cortical injury. Neurosci Lett 497:172-6
Jin, Xiaoming; Huguenard, John R; Prince, David A (2011) Reorganization of inhibitory synaptic circuits in rodent chronically injured epileptogenic neocortex. Cereb Cortex 21:1094-104

Showing the most recent 10 out of 13 publications