An estimated 200,000 new cases of epilepsy are diagnosed each year in the United States. Temporal lobe epilepsy, the most common epileptic syndrome, often develops following early unprovoked seizures and is particularly resistant to mainstream antiepileptic drugs. The hippocampal dentate gyrus is at the heart of the characteristic structural and functional changes that underlie temporal lobe epilepsy. A network of perisomatically projecting GABAergic interneurons regulates the excitability of dentate projection neurons, the granule cells. Activity and synchrony of inhibitory networks are governed by a combination of gap junctional and GABAergic chemical connections. However, whether GABAergic inhibition and electrical coupling among the perisomatic interneurons are modified during development of epilepsy and underlie the instability in network activity in epilepsy is yet to be examined. Additionally, dynamic changes in inhibitory and electrical coupling among interneurons are likely to determine the duration and spread of seizures. Understanding how activity patterns in the perisomatic inhibitory network are altered following status epilepticus and dynamically regulated during seizures will help evaluate whether pharmacological manipulation of gap junctions and GABA receptors would be effective in treating epilepsy. The hypothesis of this proposal is that status epilepticus (SE) alters non-synaptic and synaptic coupling between fast-spiking perisomatic dentate interneurons resulting in enhanced mutual inhibition which compromises feedback inhibition of projection neurons. It is further proposed that modulation of inhibitory currents and electrical coupling by pH changes that accompany neuronal activity undermine perisomatic inhibition during neuronal activity enhancing dentate excitability and contributing to epileptogenesis. The study will use pilocarpine induced status epilepticus to model development of acquired epilepsy, and a combination of anatomical, physiological and computational approaches to address the following specific questions.
Aim 1 will identify the presence of tonic GABA currents in fast-spiking basket cells and examine whether post-status enhancement of tonic GABA currents compromise perisomatic inhibition of granule cells.
Aim 2 will identify post-status changes in synaptic and electrical coupling among basket cells and their effects on dentate network excitability and synchrony.
Aim 3 will test whether activity-dependent modulation of basket cell synaptic and non-synaptic coupling by acidic pH shifts accompanying neuronal activity undermines inhibition and contributes to epileptogenesis after status epilepticus. It is anticipated that the study will identify fundamental mechanisms underlying dynamical instability of dentate network activity in acquired epilepsy.

Public Health Relevance

Acquired temporal lobe epilepsy is a disorder affecting over 1.5 million patients and is associated with long term decrease in quality of life. The experiments proposed in this study will determine if dynamic decreases in inhibition during seizures contributes to prolonged neuronal activity and development of epilepsy. It is expected that understanding the changes in inhibitory circuit function in epilepsy will lead to novel alternatives to manage patients with early unprovoked seizures and reduce the risk for developing epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069861-05
Application #
8732482
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Stewart, Randall R
Project Start
2011-09-30
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Newark
State
NJ
Country
United States
Zip Code
07103
Neuberger, Eric J; Swietek, Bogumila; Corrubia, Lucas et al. (2017) Enhanced Dentate Neurogenesis after Brain Injury Undermines Long-Term Neurogenic Potential and Promotes Seizure Susceptibility. Stem Cell Reports 9:972-984
Neuberger, Eric J; Gupta, Akshay; Subramanian, Deepak et al. (2017) Converging early responses to brain injury pave the road to epileptogenesis. J Neurosci Res :
Subramanian, Deepak; Santhakumar, Viji (2017) Lighting the Fuse: Deconstructing Complex Network Interactions Using On-Demand Seizures. Epilepsy Curr 17:174-176
Swietek, Bogumila; Gupta, Akshay; Proddutur, Archana et al. (2016) Immunostaining of Biocytin-filled and Processed Sections for Neurochemical Markers. J Vis Exp :
Gupta, Akshay; Santhakumar, Viji (2016) Illuminating the Role for Chloride Dysregulation in Network Activity. Epilepsy Curr 16:258-60
Proddutur, Archana; Santhakumar, Viji (2016) Fingerprints of Interictal Spikes: Can Imprints Deliver a Verdict on Their Role in Epilepsy? Epilepsy Curr 16:41-2
Yu, Jiandong; Proddutur, Archana; Swietek, Bogumila et al. (2016) Functional Reduction in Cannabinoid-Sensitive Heterotypic Inhibition of Dentate Basket Cells in Epilepsy: Impact on Network Rhythms. Cereb Cortex 26:4229-4314
Murugan, Madhuvika; Santhakumar, Vijayalakshmi; Kannurpatti, Sridhar S (2016) Facilitating Mitochondrial Calcium Uptake Improves Activation-Induced Cerebral Blood Flow and Behavior after mTBI. Front Syst Neurosci 10:19
Yu, Jiandong; Swietek, Bogumila; Proddutur, Archana et al. (2016) Dentate cannabinoid-sensitive interneurons undergo unique and selective strengthening of mutual synaptic inhibition in experimental epilepsy. Neurobiol Dis 89:23-35
Li, Ying; Korgaonkar, Akshata A; Swietek, Bogumila et al. (2015) Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury. Neurobiol Dis 74:240-53

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