Epilepsy is a common severe neurological disorder with one-year prevalence ~7/1,000, whose circuit mechanisms are poorly understood. Its prevalence is high among veterans. Patients with post-traumatic brain injury carry a high risk of epilepsy for decades following injury, causing considerable morbidity. At 15 years following injury 51% of the subjects in the Vietnam Head Injury Study carried a diagnosis of seizure. Clearly epilepsy is an important problem for the VA population. Acquired trauma often leads to focal imbalance between excitation and inhibition, which drives otherwise normal neural circuits into self-perpetuating oscillatory activity states manifesting as seizures on cortical surface EEG. This phenomenon clearly warrants study as it is shared by multiple neurological disorders presenting with focal seizures, including chronic focal epilepsy, which is the most commonform ofpost-traumatic epilepsy. Specifically, weneedtounderstand how individualneuronsgetrecruitedintoictaleventsinvivo,whatisthesequenceofrecruitment,howpropertiesof recruitment change with time leading to the onset and offset of ictal activity, how recruitment depends on the interactionbetweenexcitatoryneuronswithspecificclassesofinhibitoryinterneurons,andwhetherrecruitment proceedsmoreefficientlyalongcertaincircuitpathwaysmorethanothers. We will combine large scale in vivo 2-photon microscopy techniques withspecific optogenetic modulation of selected cell types and individual unit patch-clamp recordings to study theemergence and spread of focally initiated seizures in the 4-aminopyridine (4-AP) mouse model of focal ictogenesis. We propose to study and compare visual and motor cortex, two areas with different potential for ictogenicity. The 4-AP model is a reliable, well-established, model of focal neocortical seizures inducing electroencephalographic (EEG) events similar to the low-voltage fast-onset events observed in human patients with focal post-traumatic epilepsy. Comparedtootherchemo-convulsants,GABA-ergictransmissionisrelativelypreserved,making4-APanideal model for studying how normal inhibitory circuits fail to contain the spread of abnormal events driven by an excessofexcitationashasbeenarguedtooccurinpost-traumaticepilepsy.
In Aim #1, we will measure the profile of recruitment of individual neurons to the phases of progression of focal neocortical seizure events observed by EEG after 4-AP injection, and will determine how recruitment depends on cell type and position along the cortical circuit. The 3 major classes of GABA-ergic interneurons (PV+, SOM+, VIP+) will be monitored in vivo and their recruitment to seizure events characterized in layers 2/3, 4, and 5, in area V1 (the site of 4-AP injection) as well as in area V2 and the contralateral cortex. We expect cortical neurons to be differentially modulated during the interictal, pre-ictal, ictal-proper and post-ictal phases. Recruitment profiles of different neuronal types during the evolution of epileptiform activity from interictal to ictal will be informative about the role these neurons play in seizure progression. To identify universalthemesofcircuitmalfunctionwewillcompare4-APtothepilocarpinemodeloffocalictogenesis.
In Aim #2, we will use optogenetic methods to interrogate the causal role of different interneuronal types in the evolution of focal epileptiform activity from interictal to ictal and test how to stop the seizures. We expect that different interneuron classes make distinct contributions to the entrainment of local cortical circuits by ictogenic activity. This will likely depend on cortical layer. Interneurons that engage differentially during the variousphasesofseizureprogressionwillbeprimetargetsforcontrollingictalactivity. Understanding how individual neurons get recruited into seizure events in focal epilepsy and how they influenceictogenesiswillformthebasisforthefuturedevelopmentofnew,circuit-based,therapeuticstrategies targeting specific cell classes. This represents a shift of paradigm complementary to current pharmacologic approaches.

Public Health Relevance

Epilepsy is a common severe neurological disorder whose prevalence is high among veterans. Focal cortical lesions such as those induced by traumatic brain injury or stroke carry a high risk of developing chronic epilepsy. Brain areas outside the ?epileptic focus? are recruited to participate to the spread of ictal events, even though they often remain intact. This phenomenon clearly warrants study, as it is shared by many neurological disorders that present with seizures. We propose to use state-of-the art imaging and optogenetic techniques to study in vivo how neurons of different types are recruited to seizure events in a mouse model of induced focal seizures. By using optogenetics to modulate the activity of specific cell types, we will be able to infer their role in the development of the seizures as well as the best way to stop it. Understanding the role that different cell types play in the evolution of seizures after injury will yield new, circuit-based, therapeutic strategies targeting specific cell classes. This represents a shift of paradigm complementary to current pharmacologic approaches.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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VA Boston Health Care System
United States
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