While a heightened risk of seizures in Alzheimer?s Disease (AD) has been observed in sporadic studies from the 1980s to the present, the extent of comorbidity, and the implications for seizures to influence AD progression and outcomes is only now coming to be appreciated. While in the general population, the risk of epilepsy is ~1%, some studies have found the risk in AD to be up to 8-10%. The goal of the parent grant is to understand the circuit mechanisms by which neuromodulation in the basal ganglia can control seizures, with the ultimate goal of identifying new deep brain stimulation targets for epilepsy, such as the deep and intermediate layers of the superior colliculus (DLSC). While a small, but growing, number of studies have evaluated pharmacotherapy as an intervention for seizures in AD models, none, to the best of our knowledge have employed brain stimulation approaches, representing a gap in knowledge. The proposed supplement aims to address this gap in knowledge through two aims.
In Aim 1, we will test the hypothesis that open and closed-loop optogenetic activation of the superior colliculus will suppress spontaneous non-convulsive seizures in the TgF344-AD rat model of AD. This represents one of the two major seizure types seen in patients with AD.
In Aim 2, we will address the other major seizure type, temporal lobe (limbic) seizures. We will test the hypotheses that TgF344-AD rats will display enhanced limbic epileptogenesis after status epilepticus, that FgF344-AD rats will display more severe impairments in cognition after status epilepticus, and that spontaneous seizures after status epilepticus will be reduced by optogenetic stimulation of the DLSC. Through these aims, we will determine if a promising preclinical brain stimulation approach will also be useful against seizures in a model of AD, determine how AD pathology and cognitive dysfunction are impacted by an epileptogenic insult, and model both of the major seizure types observed in patients with AD.

Public Health Relevance

Epilepsy is the second most common neurological disorder. Unfortunately, current treatments for epilepsy are unable to control seizures in many patients. For this reason, identification of new methods for seizure control is a high priority. Here we will test the ability of a brain circuit to restrain seizures and prevent the development of epilepsy by activating endogenous neural circuitry that functions to resist and prevent the propagation of seizure activity. We propose to determine if recently developed optogenetic methodologies can be deployed in these structures to suppress seizures. We will explore this using several of seizures and epilepsy and simultaneously use the optogenetic approach to dissect the critical basal ganglia pathways for seizure control and identify the mechanisms by which basal ganglia can suppress seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS097762-05S1
Application #
10123790
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Churn, Severn Borden
Project Start
2016-07-15
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Elorette, Catherine; Forcelli, Patrick A; Saunders, Richard C et al. (2018) Colocalization of Tectal Inputs With Amygdala-Projecting Neurons in the Macaque Pulvinar. Front Neural Circuits 12:91
Aguilar, Brittany L; Forcelli, Patrick A; Malkova, Ludise (2018) Inhibition of the substantia nigra pars reticulata produces divergent effects on sensorimotor gating in rats and monkeys. Sci Rep 8:9369
Santos, Victor R; Kobayashi, Ihori; Hammack, Robert et al. (2018) Impact of strain, sex, and estrous cycle on gamma butyrolactone-evoked absence seizures in rats. Epilepsy Res 147:62-70
André, Emily A; Forcelli, Patrick A; Pak, Daniel Ts (2018) What goes up must come down: homeostatic synaptic plasticity strategies in neurological disease. Future Neurol 13:13-21
Aguilar, Brittany L; Malkova, Ludise; N'Gouemo, Prosper et al. (2018) Genetically Epilepsy-Prone Rats Display Anxiety-Like Behaviors and Neuropsychiatric Comorbidities of Epilepsy. Front Neurol 9:476
Lee, Yichien; Rodriguez, Olga C; Albanese, Chris et al. (2018) Divergent brain changes in two audiogenic rat strains: A voxel-based morphometry and diffusion tensor imaging comparison of the genetically epilepsy prone rat (GEPR-3) and the Wistar Audiogenic Rat (WAR). Neurobiol Dis 111:80-90
Dunn, Raymond; Queenan, Bridget N; Pak, Daniel T S et al. (2018) Divergent effects of levetiracetam and tiagabine against spontaneous seizures in adult rats following neonatal hypoxia. Epilepsy Res 140:1-7
Forcelli, Patrick A (2017) Applications of optogenetic and chemogenetic methods to seizure circuits: Where to go next? J Neurosci Res 95:2345-2356