# Astrocytic mechanisms in a new genetic model of migraine

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $507,101

## Abstract

Migraine affects 12% of the world population, and is one of the leading causes of disability worldwide. Yet
surprisingly little is known about the basic features of this disease. We helped develop a new mouse genetic
model of migraine, and we now propose to examine its mechanisms. The casein kinase 1 delta (CK1d) mouse
expresses a mutation from a family with inherited migraine with aura. We found that CK1d mice had two key
phenotypes relevant to migraine: an increased sensory network response to a migraine trigger, and an
increased susceptibility to cortical spreading depression (CSD), which underlies the migraine aura. While our
initial efforts focused on potential neuronal mechanisms underlying this network excitability, we have been able
to rule those out, and now focus on increasing evidence that the CK1d mutation exerts its effects through
astrocytes - specifically through impaired uptake of glutamate and potassium. Our first aim will directly examine
glutamate and K+ reuptake on CK1d animals and wild type littermates, using a combination of in vivo two
photon microscopy and whole cell electrophysiological recordings. Our hypothesis is that due to its effects on
astrocyte syncitial function, the CK1d mutation slows glutamate and K+ reuptake. We will confirm this with
CK1d inhibition and overexpression, and direct inhibition of the connexin43 protein (Cx43), a CK1d target. The
second aim will take a similar approach while examining CSD, and the third aim will examine sensory network
function. Our hypothesis is that impaired astrocytic uptake is the common mechanism that links both
phenotypes. If successful we will be able to assess whether the CK1d mutation is necessary and sufficient for
the migraine phenotype, and by what specific mechanism(s) it exerts its effects. This work could be important
because it would add significantly to evidence that astrocytic reuptake, like neuronal excitability, is a viable
path to migraine induction. A second important aspect is that, although the CK1d mutation is undoubtedly rare,
it contrasts with all other monogenic migraine models in that mutation carriers have normal migraine attacks
(as opposed to attacks associated with hemiplegia), and thus could be more relevant to the majority of
migraine sufferers.

## Key facts

- **NIH application ID:** 10159985
- **Project number:** 5R01NS104742-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kevin Christopher Brennan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,101
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159985

## Citation

> US National Institutes of Health, RePORTER application 10159985, Astrocytic mechanisms in a new genetic model of migraine (5R01NS104742-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159985. Licensed CC0.

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