GABAergic neurons and NaV1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

AbstractCortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons’ excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K+ build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmission is not required for optogenetic CSD initiation, but glutamatergic transmission is implicated in CSD propagation. Thus, our results reveal the key role of hyper-activation of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine.

Download Full-text

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1614447114 ◽

2017 ◽

Vol 114 (9) ◽

pp. 2401-2406 ◽

Cited By ~ 23

Author(s):

Stuart M. Cain ◽

Barry Bohnet ◽

Jeffrey LeDue ◽

Andrew C. Yung ◽

Esperanza Garcia ◽

...

Keyword(s):

Mechanism Of Action ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Brain Structures ◽

Familial Hemiplegic Migraine ◽

Cellular Level ◽

Systemic Administration ◽

Glutamatergic Synaptic Transmission ◽

Subcortical Brain Structures

Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wild-type (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the CaV2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of CaV2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.

Download Full-text

Widespread c-Fos expression after cortical spreading depression; possible differences between two types of animal models of familial hemiplegic migraine 2

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.2666 ◽

2017 ◽

Vol 381 ◽

pp. 947

Author(s):

M. Unekawa ◽

K. Ikeda ◽

Y. Tomita ◽

K. Kawakami ◽

N. Suzuki

Keyword(s):

Animal Models ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Fos Expression

Download Full-text

Role of amygdala in feeding and drinking induced by single cortical spreading depression in the rat

Physiology & Behavior ◽

10.1016/0031-9384(82)90234-7 ◽

1982 ◽

Vol 29 (4) ◽

pp. 649-656 ◽

Cited By ~ 4

Author(s):

M SHIBATA

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression

Download Full-text

Cortical Spreading Depression—New Insights and Persistent Questions

Cephalalgia ◽

10.1111/j.1468-2982.2009.01983.x ◽

2009 ◽

Vol 29 (10) ◽

pp. 1115-1124 ◽

Cited By ~ 90

Author(s):

A Charles ◽

KC Brennan

Keyword(s):

Brain Injury ◽

Animal Models ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Exact Role ◽

Definitive Evidence ◽

Meaningful Information ◽

Human Disorders ◽

Functional Consequences

Since its original extensive description by Leao in 1944, thousands of publications have characterized the phenomenon of cortical spreading depression (CSD). Despite the attention that CSD has received over more than six decades, however, many fundamental questions regarding its initiation, propagation, functional consequences, and relationship to migraine and other human disorders remain unanswered. Advances in genetics and cellular imaging have led to important insights into the basic mechanisms of CSD, with increasing attention focused on specific neuronal ion channels, neurotransmitters and neuromodulators. In addition, there is growing recognition that astrocytes and the vasculature may play an active, rather than simply a passive or reactive role in CSD. Several recent descriptions of CSD in humans in the setting of brain injury provide definitive evidence that this phenomenon can occur and have important functional consequences in the human brain. Although the exact role of CSD in migraine has yet to be conclusively established, there is strong evidence that the investigation of CSD in animal models can provide meaningful information about migraine that can be translated into the clinical setting. This review will briefly address the extensive work that has been done on CSD over more than half a century, but focus primarily on more recent studies with a particular emphasis on relevance to migraine.

Download Full-text