In mesial temporal lobe epilepsy (TLE), an initial precipitating event triggers a progressive process of cell death and circuit reorganization that renders neural networks hyperexcitable and susceptible to abnormal synchronized activity that manifests as spontaneous recurring seizures. TLE is one of the most common and difficult to treat forms of focal epilepsy and is associated with hippocampal neurodegeneration that spares the CA2 region. In chronically epileptic animals seizures propagate through the hippocampus despite widespread cell death in CA1 and CA3, suggesting that epileptic activity may be generated in or conveyed through surviving CA2 circuitry. Furthermore, accumulating evidence suggests that CA2 may have an important role controlling hippocampal network excitability and synchrony, but the underlying mechanisms remain unknown. Considering together the resilience of the CA2 region and its role controlling network excitability, I hypothesize that in TLE the CA2 region acts as a critical hub supporting the generation and propagation of epileptiform activity in the hippocampal network. In an in vitro model of pharmacologically-induced epileptiform activity acute silencing of CA2 PNs reduced population bursting in CA1. Preliminary data from the pilocarpine mouse model of TLE suggests enhanced excitatory synaptic input to CA2 in epileptic mice and increased intrinsic excitability of CA2 PNs. Furthermore, preliminary data from a collaborative study between our laboratory and that of Helen Scharfman at the Nathan Kline Institute suggest that chronic silencing of CA2 in pilocarpine- treated mice may reduce the frequency of spontaneous seizures. The contribution of the CA2 subfield to hippocampal circuitry and physiology remains incompletely understood and changes to CA2 circuitry in TLE have not been investigated. In addition to receiving input from dentate gyrus granule cells and CA3 PNs, CA2 PNs receive exceptionally strong excitatory input from the entorhinal cortex. In turn, CA2 axons project forward to CA1, extend backwards throughout CA3, and form local recurrent connections that excite other CA2 PNs. CA2 back-projections also enter the hilus of the DG, but this circuit has not been characterized. Thus, CA2, CA3, and the DG together form a highly interconnected recurrent network that may become a hyperexcitable hub under pathological conditions. It is essential to define how CA2 circuitry changes in chronic epilepsy, and in turn, how these altered circuits contribute to pathophysiological activity. To address these gaps in knowledge, I will use optogenetic approaches in vitro and in vivo using the Amigo2-Cre mouse line, which drives expression selectively in CA2 pyramidal neurons. Using the pilocarpine mouse model of TLE, I will characterize CA2 circuitry in normal and epileptic mice and identify the changes to CA2 circuitry that accompany epileptogenesis and determine if modulation of CA2 activity influences chronic seizures. These experiments will advance our understanding of the role of the CA2 region in controlling hippocampal network excitability and the generation of seizures in a model of mesial temporal lobe epilepsy.

Public Health Relevance

Epilepsy is one of the most common neurological disorders, affecting approximately 1% of the population, yet roughly one third of these patients experience refractory epilepsy with seizures that are not effectively controlled by available antiepileptic drugs. The CA2 subfield of the hippocampus exhibits a unique genetic and molecular profile and is resilient to hippocampal sclerosis in mesial temporal lobe epilepsy (MTLE). The experiments outlined in this proposal will reveal how CA2 circuitry changes in MTLE and provide insight into whether therapeutic approaches that target CA2 could be used to mitigate or prevent seizures.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Leenders, Miriam
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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