# Control of Axon Initial Segment in Epilepsy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $673,584

## Abstract

Temporal lobe epilepsy (TLE) is the most common epilepsy in adults, and it is frequently refractory to current
anti-epileptic drugs, with treatments often exerting a variety of debilitating side effects. A major barrier for the
development of novel treatment strategies is our insufficient understanding of the precise cellular and circuit
mechanisms underlying TLE. A centrally important but unresolved question in TLE concerns the mechanisms
underlying the excessive, dysregulated production of action potentials at the axon initial segment (AIS) of
excitatory principal cells (PCs). Synaptic control of AIS is provided by a unique, evolutionarily conserved,
GABAergic cell-type, the axo-axonic cells (AACs). AACs form synaptic contacts exclusively with the AIS of
PCs, placing AACs in a strategic position to control action potential generation. However, due to technical
limitations, our knowledge about the in vivo function and regulation of AACs in the normal and epileptic
hippocampus has been extremely limited. Here we propose to employ a combination of recent technical
breakthroughs to test hypotheses about the in vivo functional effects, activity dynamics and efficacy of AAC-
mediated control of AIS in mouse models of chronic TLE. The planned project will also determine if it is
possible to mitigate epilepsy-related pathologically hyperactive circuits and cognitive deficits through
interventions selectively directed at the AAC-dependent, endogenous GABAergic processes regulating AIS in
chronic epilepsy. The proposed project aims to fill a major knowledge gap and address long-standing
controversies concerning the interneuronal regulation of AIS in epilepsy by leveraging expertise in novel large-
scale, high-resolution in vivo functional imaging techniques in combination with advanced electrophysiological,
behavioral, optogenetic and computational modeling techniques in the CA1 region of the mouse hippocampus.
It is anticipated that defining the function, regulation and therapeutic potential of AACs in TLE will have a
significant impact by advancing our understanding of key circuit control mechanisms in chronic epilepsy and
aid the future development of novel anti-epileptic treatment strategies.

## Key facts

- **NIH application ID:** 10183360
- **Project number:** 1R01NS121106-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Attila Losonczy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $673,584
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183360

## Citation

> US National Institutes of Health, RePORTER application 10183360, Control of Axon Initial Segment in Epilepsy (1R01NS121106-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10183360. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*