# Role of Perineuronal Nets in Epilepsy

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $368,348

## Abstract

PROJECT SUMMARY/ABSTRACT
Approximately 50 million people worldwide live with epilepsy, a syndrome characterized by repeated,
unprovoked seizures that manifest with a combination of altered behavior and abnormal electric discharges of
populations of neurons in the brain. Seizures result from impairment of excitatory-inhibitory (E-I) balance.
Enhancement of inhibitory GABAergic function is a common pharmacological strategy. Not surprisingly,
GABAergic interneurons in the cortex and hippocampus have been well studied, and their role in dampening
excitatory output from these structures is well established. GABAergic interneurons tend to be fast-spiking cells
(up to 800Hz!), which compensate for their small number by a high level of activity with each action potential
causing GABA release from their terminals. A majority of these fast-spiking neurons are surrounded by a layer
of dense extracellular matrix that Golgi termed perineuronal nets (PNNs) over 120 years ago. These are
composed of glycosaminoglycanes, negatively charged glycoproteins formed from a superfamily of proteins that
cover the cell soma, proximal dendrites and axon initial segment. Their role is not well known but believed to aid
in cell differentiation, neural protection and cortical plasticity. During the last grant cycle studying tumor-
associated epilepsy, we made an unexpected discovery suggesting that PNNs alter the neuronal membrane
capacitance, allowing them to fire at supra-physiological rates. Specially, proteolytic enzymes released from the
tumor digest PNNs, thereby increasing membrane capacitance and slowing the firing rates of inhibitory neurons,
leading to seizures. We now hypothesize that PNNs may be more generally the target of acquired epilepsy,
where proteolysis of extracellular matrix and tissue remodeling are common. Hence, we propose to study PNN
integrity and its role in epileptogenesis more broadly across different mouse models of acquired epilepsy and in
tissues from epilepsy patients. We hypothesize that PNNs define the placement of astrocytes near synapses to
aid uptake of ions and neurotransmitters; that release of matrix-degrading enzymes from reactive astrocytes
destroy PNNs, thereby slowing their firing rate. Together these changes may lead to epilepsy. These studies are
conceptually novel and may suggest a completely different treatment approach to epilepsy, namely targeting
proteolytic enzymes to ameliorate this disease.

## Key facts

- **NIH application ID:** 9973987
- **Project number:** 2R01NS036692-19A1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** HARALD W SONTHEIMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,348
- **Award type:** 2
- **Project period:** 1997-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973987

## Citation

> US National Institutes of Health, RePORTER application 9973987, Role of Perineuronal Nets in Epilepsy (2R01NS036692-19A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9973987. Licensed CC0.

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