# Microcircuits of the Subiculum and Epilepsy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $345,625

## Abstract

Project Summary / Abstract
A prominent theory regarding the development of epileptic hyper-synchronization in human and animal
models of temporal lobe epilepsy proposes a key role for the specific down-regulation of the expression of
the KCC2 transporter in subicular pyramidal cells. As KCC2 is essential to maintain the low intracellular
chloride concentrations required for hyperpolarizing GABAergic signaling, loss of KCC2 expression would
impair GABAergic inhibition and trigger a series of events leading to the emergence of subicular-initiated
interictal activity. Furthermore, interictal discharges coupled to synaptic plasticity would result in interictal-
ictal transitions and spread hyper-excitability to extra-hippocampal regions.
In summary, if the essential aspects of this KCC2-based mechanistic theory of epileptogenesis were
correct, the selective pharmacological reduction of KCC2 transporter activity in a naïve subiculum should
be sufficient to generate epileptiform activity ranging from interictal-like to, possibly, full ictal-like events.
Although this prediction was supported by computational modeling, direct experimental evidence has not
yielded definitive results.
Our preliminary data show that the application of highly selective KCC2 antagonists on isolated mini-slices
of the mouse subiculum generate synchronous interictal-like bursting that depends on depolarizing
GABAergic signaling, but are not, apparently, sufficient to trigger ictal-interictal transitions.
We will take advantage of a variety of state of the art techniques (simultaneous patch-clamp recordings
from synaptically coupled and uncoupled cells, optogenetic control of specific neuronal populations, and
high resolution anatomical reconstructions) to investigate the impact of this type of pharmacologically-
induced epileptiform activity in subicular mini-slices. We will explore its consequences on intrinsic and
synaptic plasticity, reveal the underlying mechanisms played by different interneuron subtypes, and
explore whether additional epileptogenic changes and/or synaptic input from extra-subicular regions are
necessary to drive interictal-like to ictal-like transitions.

## Key facts

- **NIH application ID:** 10241353
- **Project number:** 5R01NS096092-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Gianmaria MACCAFERRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,625
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241353

## Citation

> US National Institutes of Health, RePORTER application 10241353, Microcircuits of the Subiculum and Epilepsy (5R01NS096092-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10241353. Licensed CC0.

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