# Microcircuits of the Subiculum and Epilepsy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $466,548

## Abstract

Project Summary / Abstract
The subiculum is a critical output network of the hippocampal formation and participates in a variety of important
physiological functions. However, in pathological conditions such as temporal lobe epilepsy, its own intrinsic
circuits may initiate hyper-synchronous discharges leading to generalized seizures. In fact, a prominent theory
of TLE proposes a key role for the subicular-specific down-regulation of the KCC2 potassium chloride co-
transporter in the alteration of GABAergic inhibition that leads to the generation of pathological activity.
During the previous cycle, we have studied the isolated subicular circuitry in vitro. We have shown with direct
and sophisticated techniques that subicular pyramidal cells are highly reciprocally interconnected and require
physiological GABAergic inhibition to prevent the emergence of epileptiform self-synchronization. Furthermore,
we have shown that the subicular circuitry is sufficient to initiate epileptiform activity when KCC2 function is
pharmacologically blocked.
Here, we propose to study the critical role of specific populations of local GABAergic interneurons, (parvalbumin-
somatostatin- and neuron derived neurotrophic factor-expressing cells) as well as pyramidal cell functional
diversity under conditions of reduced KCC2 activity. We have found that the exposure of subicular tissue to brain
derived neurotrophic factor (BDNF, which is abundantly released in the epileptic brain and is known to
downregulated KCC2 in neural membranes) produces a surprising (and yet unreported) change in GABAergic
network signaling. The experiments proposed in the application will study the biophysical, pharmacological,
anatomical and network mechanisms involved in this (previously unreported) GABA-dependent recruitment of
excitatory polysynaptic pathways.
Given the lack of seizure control in ~30% of TLE cases, a new mechanistic understanding of the chain of events
leading to the initiation and/or propagation of epileptiform activity in central networks is of critical importance for
the development of novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10877524
- **Project number:** 2R01NS096092-06A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Gianmaria MACCAFERRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,548
- **Award type:** 2
- **Project period:** 2018-09-30 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877524

## Citation

> US National Institutes of Health, RePORTER application 10877524, Microcircuits of the Subiculum and Epilepsy (2R01NS096092-06A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10877524. Licensed CC0.

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