# Control of Circuit Hyperexcitability by Endogenous Opioids in Epilepsy

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2021 · —

## Abstract

Epilepsy is a devastating neurologic condition that affects about 2 million Americans and is often resistant
to medical treatment. Animal studies have demonstrated that epilepsy is associated with compensatory
changes in the brain, which includes the aberrant rewiring of neuronal circuits. In particular, epilepsy is
associated with altered connectivity in the hippocampus, a region of the brain that is frequently the focal point
for the initiation of seizures. One particular hippocampal circuit rearrangement associated with epilepsy
involves the growth (“sprouting”) of hippocampal granule cell axons (the mossy fibers) in a retrograde direction.
These sprouted fibers could directly cause hippocampal hyperexcitability by forming recurrent excitatory
circuits, or alternatively increase the activity of inhibitory mechanisms and prevent seizures.
 Using a combination of novel approaches, our recent work determined that these fibers directly drive
retrograde excitation and hyperexcitable circuit function. Interestingly, a large proportion of these retrograde
projections derive from newly generated, adult-born granule cell neurons, which are produced in large numbers
after seizures and undergo aberrant maturation and circuit integration. This suggests that these adult-born
neurons might contribute substantially to seizure initiation and propagation, if they alter the balance of
excitation and inhibition in the hippocampus.
 At the same time, sprouted mossy fibers have long been known to produce multiple peptide
neurotransmitters, which include endogenous opioid peptides. Although the receptors for these peptides are
known to potently control neuronal excitability throughout the brain, the functional importance of endogenous
peptides in the control of hyperexcitability in epilepsy has not been explored. Notably, even basic questions
regarding the conditions under which these peptides are released, the functions of specific receptors in
different cell types, and whether these peptides modulate seizure frequency or severity in epilepsy are not
known. Thus, their role during epileptogenesis remains a long-standing unanswered question in the field, and
represents a therapeutic opportunity.
 With this proposal, we will answer fundamental questions regarding the roles of these peptides in the
control of hippocampal function in epilepsy, and how potential alterations in opioid peptide signaling
mechanisms due to enhanced neurogenesis might overwhelm endogenous control mechanisms that prevent
seizures. We have combined various lines of genetically modified mice, which allow us to specifically label and
optogenetically control different subsets of hippocampal granule cells in live tissue. We will induce
experimental epilepsy using the well-established pilocarpine model of epilepsy, and use electrophysiologic
recording techniques to study the functional roles of these peptides in the hippocampal circuit. Furthermore, we
will use additional genetic manipulations to ...

## Key facts

- **NIH application ID:** 10106465
- **Project number:** 5I01BX004938-02
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Eric Schnell
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106465

## Citation

> US National Institutes of Health, RePORTER application 10106465, Control of Circuit Hyperexcitability by Endogenous Opioids in Epilepsy (5I01BX004938-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10106465. Licensed CC0.

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