# The role of CA2 circuits in temporal lobe epilepsy

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $45,520

## Abstract

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 influen...

## Key facts

- **NIH application ID:** 10018472
- **Project number:** 5F31NS113466-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Alexander Craig Whitebirch
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018472

## Citation

> US National Institutes of Health, RePORTER application 10018472, The role of CA2 circuits in temporal lobe epilepsy (5F31NS113466-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018472. Licensed CC0.

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