# Inhibitory Controls of Thalamic Neurons

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $457,536

## Abstract

The brain has likely evolved multiple control mechanisms to regulate activity and keep it
in a robust operational state. Occasionally these regulatory mechanisms break down,
and uncontrolled activity in the form of epileptic seizures ensues. This is especially
evident in the syndrome of primary generalized epilepsy in which global seizures
suddenly arise from a normal behavioral state. A form of primary generalized epilepsy,
absence epilepsy, is expressed in a network composed of widespread regions of
neocortex and a subcortical structure, the thalamus, that together form the
thalamocortical circuit. Childhood absence seizures are characterized by widespread
synchronized thalamocortical activity, EEG 3/s spike and wave discharge, and loss of
consciousness. Validated genetic rat and mouse models of absence epilepsy have
identified some of the thalamic and cortical microcircuit elements, i.e. the individual
neuron types and their synaptic connections that participate in the epileptic network, yet
it remains unclear how the circuit suddenly and unpredictably switches its state from
that of normal functioning to seizure generating and back. Recent evidence suggests
that in one central node of the thalamocortical network, the reticular thalamus (RT), a
single type of branch of RT neuron axonal output is specifically susceptible to sporadic
failures that might explain sudden seizure onset. Pilot data indicate that this internal
branch, which regulates RT itself, can fail in a use-dependent way that would lead to
uncontrolled RT activity that can precipitate seizures. Further, Scn8a deficient mice,
with frequent absence seizures, show increased intra-RT failures, indicating a causative
role. Only recently have the methods become available to directly study axon function,
allowing us for the first time ask questions about how the selective failure of
neurotransmission in axon branches can occur. Experiments will utilize high resolution 2
photon imaging and electrophysiology to visualize the different branches of RT axons
and address the novel hypothesis that failure, i.e. the inability to send efferent synaptic
signals, through individual output axon branches and their synaptic release sites could
be causative in epilepsy. Aims will determine the conditions in which selective branch
failure of intra-RT vs RT output axons to the dorsal thalamus occurs, and the
mechanisms for the failure, whether they be through failure of action potential
generation or through decreased probability of synaptic release, and whether failure
mechanisms may apply more broadly to epilepsies. The results of these studies could
inform the development of potential new epilepsy treatment approaches that would
prevent the failure of key output branches.

## Key facts

- **NIH application ID:** 10137314
- **Project number:** 5R01NS034774-25
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** John R Huguenard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,536
- **Award type:** 5
- **Project period:** 1996-07-22 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137314

## Citation

> US National Institutes of Health, RePORTER application 10137314, Inhibitory Controls of Thalamic Neurons (5R01NS034774-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137314. Licensed CC0.

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