Elucidating the basic mechanisms by which a normal brain is transformed into an epileptic brain has been a holy grail of epilepsy research for decades. If the mechanisms of epileptogenesis can be understood, then new treatments and therapies can be designed to target these processes to prevent - and possibly cure - epilepsy. While years of research have revealed a multitude of changes that occur during epileptogenesis, one basic problem has been distinguishing changes that mediate epileptogenesis from changes that are associated with the disease, but play no causal role. This problem is evident for almost all existing models of epilepsy, which produce widespread brain damage and cellular changes, thereby making the proximal cause of the disease difficult to ascertain. For the present proposal, we make a pivotal advance by utilizing a novel mouse model of epilepsy generated in the first term of this grant, in which epilepsy develops following conditional, inducible deletion of the mTOR pathway inhibitor phosphatase and tensin homologue (PTEN) from a subset (>5%) of hippocampal dentate granule cells (DGC). Excessive activation of the mTOR pathway is implicated in the development of temporal lobe epilepsy, and the effect of this deletion - to induce the abnormal integration of newborn DGC - is important because abnormal newborn DGC are a hallmark pathology of temporal lobe epilepsy, and are suspected of causing the disease. Our study provides direct evidence that abnormal DGC can cause epilepsy. Having demonstrating that abnormal DGC can be a proximal cause of epilepsy, we now seek to elucidate the mechanism(s) by which these cells promote seizures. Our guiding hypothesis is that abnormal DGCs promote epileptogenesis initially through cell-intrinsic increases in connectivity and activity, and secondarily by inducing changes among neighboring granule cells and their downstream targets. To test this hypothesis, we will determine the primary features of abnormal cells in SA1, the temporal associations between primary and secondary changes and epileptogenesis in SA2, and the functional significance of these changes in SA3 and 4.

Public Health Relevance

The present proposal utilizes a novel mouse model of epilepsy, in which the brain malformation that causes the disease can be genetically controlled by the investigator. Using this model, we will gain a unique window into the series of brain changes that lead to epilepsy, which will provide a roadmap for the development of new treatments for the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DBD-M (08))
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Arya, Ravindra; Wilson, J Adam; Fujiwara, Hisako et al. (2018) Electrocorticographic high-gamma modulation with passive listening paradigm for pediatric extraoperative language mapping. Epilepsia 59:792-801
Danzer, Steve C (2018) Contributions of Adult-Generated Granule Cells to Hippocampal Pathology in Temporal Lobe Epilepsy: A Neuronal Bestiary. Brain Plast 3:169-181
Arya, Ravindra; Aungaroon, Gewalin; Zea Vera, Alonso et al. (2018) Fosphenytoin pre-medication for pediatric extra-operative electrical stimulation brain mapping. Epilepsy Res 140:171-176
Wulsin, Aynara C; Franco-Villanueva, Ana; Romancheck, Christian et al. (2018) Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy. PLoS One 13:e0197955
Santos, Victor R; Pun, Raymund Y K; Arafa, Salwa R et al. (2017) PTEN deletion increases hippocampal granule cell excitability in male and female mice. Neurobiol Dis 108:339-351
Arya, Ravindra; Wilson, J Adam; Fujiwara, Hisako et al. (2017) Presurgical language localization with visual naming associated ECoG high- gamma modulation in pediatric drug-resistant epilepsy. Epilepsia 58:663-673
Hosford, Bethany E; Rowley, Shane; Liska, John P et al. (2017) Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression. Sci Rep 7:18015
Zea Vera, Alonso; Aungaroon, Gewalin; Horn, Paul S et al. (2017) Language and motor function thresholds during pediatric extra-operative electrical cortical stimulation brain mapping. Clin Neurophysiol 128:2087-2093
Rowley, Shane; Sun, Xiaofei; Lima, Isabel V et al. (2017) Cannabinoid receptor 1/2 double-knockout mice develop epilepsy. Epilepsia 58:e162-e166
LaSarge, Candi L; Pun, Raymund Y K; Muntifering, Michael B et al. (2016) Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells. Neurobiol Dis 96:105-114

Showing the most recent 10 out of 31 publications