Non-canonical glutamate signaling in a genetic model of migraine with aura

Parker, Patrick D.; Suryavanshi, Pratyush; Melone, Marcello; Sawant-Pokam, Punam A.; Reinhart, Katelyn M.; Kaufmann, Dan; Theriot, Jeremy; Pugliese, Arianna; Conti, Fiorenzo; Shuttleworth, C. William; Pietrobon, Daniela; Brennan, KC

doi:10.1016/j.neuron.2020.11.018

Cited by 50 publications

(45 citation statements)

References 125 publications

(161 reference statements)

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“…As with CACNA1A mutations, GABA release is not affected in FHM2 because α2 Na/K-ATPase is not appreciably expressed on astrocyte processes around GABAergic terminals ( Cholet et al, 2002 ; Capuani et al, 2016 ). Consistent with these findings, FHM2 knock-in mice have a low CSD induction threshold and spontaneously generate the glutamate plums mentioned above ( Leo et al, 2011 ; Parker et al, 2021 ).…”

Section: Introductionsupporting

confidence: 75%

“…Therefore, increased glutamate release in FHM1 knock-in mice is consistent with the enhanced susceptibility to CSD ( Pietrobon and Brennan, 2019 ). Indeed, foci of glutamate “plumes” spontaneously bursting in the cortex of awake ATP1A2 knock-in mice, a model of FHM2, have recently been demonstrated by expressing a fluorescent glutamate reporter in the cortex ( Parker et al, 2021 ). The same study also showed that a surge of glutamate plumes preceded the onset of CSD as hypothesized before.…”

Section: Introductionmentioning

confidence: 99%

“…The transmembrane Na + gradient it creates as it takes up K + is essential for uptake of glutamate by astrocyte processes around excitatory synapses ( Cholet et al, 2001 ; Petit et al, 2021 ). Accordingly, ATP1A2 hypofunction caused by FHM2 mutations leads to reduced K + and glutamate uptake as demonstrated both in vitro and in knock-in mice, in vivo ( Capuani et al, 2016 ; Parker et al, 2021 ). As with CACNA1A mutations, GABA release is not affected in FHM2 because α2 Na/K-ATPase is not appreciably expressed on astrocyte processes around GABAergic terminals ( Cholet et al, 2002 ; Capuani et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Eren-Koçak

Dalkara

2021

Front. Pharmacol.

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Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K+, Na+, and Ca+2 channels, have been reported to be disturbed in both depression and migraine. Ion channels and energy supply to synapses not only change excitability of neurons but can also mediate the induction and maintenance of inflammatory signaling implicated in the pathophysiology of both disorders. In this respect, Pannexin-1 and P2X7 large-pore ion channel receptors can induce inflammasome formation that triggers release of pro-inflammatory mediators from the cell. Here, the role of ion channels involved in the regulation of excitation-inhibition balance, synaptic energy homeostasis as well as inflammatory signaling in migraine and depression will be reviewed.

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Section: Introductionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Eren-Koçak

Dalkara

2021

Front. Pharmacol.

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“…2C ). The triggering mechanism of these isolated events is not known, but may reflect focal changes in cortical hyperexcitation 31 or vascular insufficiency, since cerebral autoregulation may be impaired in some forms of epilepsy. 68 , 69 …”

Section: Discussionmentioning

confidence: 99%

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Aiba

Noebels

2021

Brain

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Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link depolarizing molecular defects in Ca2+ flux, Na+ current in interneurons, and glial Na+-K+ ATPase with SD susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining SD threshold. In contrast, although gene mutations in voltage-gated potassium ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility, it is not known whether epileptogenic mutations that regulate membrane repolarization also modify SD threshold and propagation. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is an SD modulatory gene with significant control over the seizure-SD transition threshold, bihemispheric cortical expression, and diurnal temporal susceptibility. Chronic DC-band cortical EEG recording from behaving conditional Kcnq2 deletion mice (Emx1cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and SD. In contrast to the related potassium channel deficient model, Kv1.1-KO mice, spontaneous cortical SDs in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the nonselective Kv7.2 inhibitor XE991 to Kv1.1-KO mice reproduced the Kcnq2 cKO-like SD phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents directly and actively modulate SD properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical SD threshold, whereas pharmacological Kv7.2 activators elevate the threshold to multiple depolarizing and hypometabolic SD triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive SD regulatory gene, and point to SD as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as a potential adjunctive therapeutic target to inhibit SD incidence.

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“…Since CSF amino acid concentrations are assumed to be similar to that of brain extracellular fluids [17], the increased CSF glutamate levels found in our study could be toxic and leading to neuronal damage [18,19], thus contributing to cognitive impairment and dementia observed in MELAS patients [20,21]. An imbalance between release and reuptake with an excess of glutamate in the synapses inducing cortical hyperexcitability, has been implicated in migraine pathophysiology [22,23] and epileptic seizures [24,25], which both are common manifestations in MELAS patients [6,26]. In addition, neuronal hyperexcitability has been proposed as a cellular pathogenic basis of stroke-like episodes [8], and the astrocyte dysfunction and neuron-astrocyte uncoupling caused by ATP deficiency is considered to be one of the critical mechanisms [8,9].…”

Section: Discussionmentioning

confidence: 66%

Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome

Guerrero-Molina¹,

Morales-Conejo

Delmiro

et al. 2022

J Neurol

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Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients. Methods This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined. Results Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 μmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 μmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS. Conclusions Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.

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Non-canonical glutamate signaling in a genetic model of migraine with aura

Cited by 50 publications

References 125 publications

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome

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