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

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

doi:10.1101/2020.01.02.891770

Cited by 9 publications

(15 citation statements)

References 69 publications

(88 reference statements)

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“…Interestingly, FHM2 knock-in mice, having reduced rate of glutamate clearance at cortical excitatory synapses (Leo et al, 2011;Capuani et al, 2016;Parker et al, 2021), show facilitation of NMDA spikes in L5 PC tuft dendrites in cingulate cortex slices, which is correlated with enhanced sensitivity to a migrainerelevant head pain trigger (Romanos et al, 2020); they also show enhanced activation of extrasynaptic GluN1-N2B NMDA receptors in L2/3 PC apical dendrites in barrel cortex slices, whose inhibition rescues the facilitation of experimental CSD (Crivellaro et al, 2021). In vivo, opposite effects of FHM1 mutations on the generation of NMDA and Ca spikes are predicted on the basis of the enhanced FDDI in FHM1 mice (Murayama et al, 2009) and the predicted enhanced excitatory transmission at the L1 topdown synaptic inputs and enhanced activation of the disinhibitory VIP IN-SOM IN-PC microcircuit.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Feedback Inhibition Due to Increased Recruitment of Somatostatin-Expressing Interneurons and Enhanced Cortical Recurrent Excitation in a Genetic Mouse Model of Migraine

et al. 2022

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Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at cortical synapses between pyramidal cells (PCs) and fast-spiking interneurons (FS INs) in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory (E/I) balance in specific circuits is a key pathogenic mechanism. Here, we investigated the cortical layer 2/3 (L2/3) feedback inhibition microcircuit involving somatostatin-expressing (SOM) INs in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca V 2.1. Unitary inhibitory neurotransmission at SOM IN-PC synapses was unaltered while excitatory neurotransmission at both PC-SOM IN and PC-PC synapses was enhanced, because of increased probability of glutamate release, in FHM1 mice. Short-term synaptic depression was enhanced at PC-PC synapses while short-term synaptic facilitation was unaltered at PC-SOM IN synapses during 25-Hz repetitive activity. The frequency-dependent disynaptic inhibition (FDDI) mediated by SOM INs was enhanced, lasted longer and required shorter high-frequency bursts to be initiated in FHM1 mice. These findings, together with previous evidence of enhanced disynaptic feedforward inhibition by FS INs, suggest that the increased inhibition may effectively counteract the increased recurrent excitation in FHM1 mice and may even prevail in certain conditions. Considering the involvement of SOM INs in c oscillations, surround suppression and context-dependent sensory perception, the facilitated recruitment of SOM INs, together with the enhanced recurrent excitation, may contribute to dysfunctional sensory processing in FHM1 and possibly migraine.

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Section: Discussionmentioning

confidence: 99%

Enhanced Feedback Inhibition Due to Increased Recruitment of Somatostatin-Expressing Interneurons and Enhanced Cortical Recurrent Excitation in a Genetic Mouse Model of Migraine

et al. 2022

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“…Recent studies using a fluorescent glutamate reporter demonstrate plumes of noncanonical glutamate release at SD initiation and the wavefront during SD propagation, likely mediated by spontaneous synaptic release and facilitated by impaired astrocyte clearance of glutamate. 144 In addition to glutamate, SD produces accumulation of other amino acids (serine, taurine, glycine, aspartate). 143 SD can collapse the perivascular space, impairing glymphatic flow which may impact clearance of proteins and other macromolecules from the interstitium.…”

Section: Physiology Of Cortical Spreading Depressionmentioning

confidence: 99%

Anatomy and Physiology of Headache

Harriott

Orlova

2022

Semin Neurol

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Headache disorders can produce recurrent, incapacitating pain. Migraine and cluster headache are notable for their ability to produce significant disability. The anatomy and physiology of headache disorders is fundamental to evolving treatment approaches and research priorities. Key concepts in headache mechanisms include activation and sensitization of trigeminovascular, brainstem, thalamic, and hypothalamic neurons; modulation of cortical brain regions; and activation of descending pain circuits. This review will examine the relevant anatomy of the trigeminal, brainstem, subcortical, and cortical brain regions and concepts related to the pathophysiology of migraine and cluster headache disorders.

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“…This discrepancy might indicate that spontaneous SD generation in Scn1a +/RX mice differs from commonly studied SD models. In a model of type-2 familial hemiplegic migraine, spontaneous SD arises as a consequence of localized glutamate deregulation associated with genetically impaired astrocytes 28 . Such a mechanism is unlikely to explain the SD susceptibility of the sodium channel deficient mouse studied here.…”

Section: Spontaneous Cortical Sd Characteristics Of Scn1a Deficient M...mentioning

confidence: 99%

A hyperthermic seizure unleashes a surge of spreading depolarizations inScn1adeficient mice

Aiba

Ning

Noebels

2022

Preprint

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Objective: Spreading depolarization (SD) is a massive wave of cellular depolarization that slowly migrates across brain gray matter. SD is frequently generated following brain injury and is associated with various acute and chronic neurological deficits. Here we report that spontaneous cortical SD waves are a common EEG abnormality in the Scn1a deficient mouse model (Scn1a+/R1407X). Method: Chronic DC-band EEG recording detected SDs, seizures, and seizure-SD complexes during prolonged monitoring in awake adult Scn1a+/R1407X mice. The effect of hyperthermic seizure and memantine was tested. Results: The spontaneous incidence of events is low and varied among animals, but SDs outnumber seizures. SD waves almost always spread unilaterally from parietal to frontal cortex. On average, spontaneous SD frequency robustly increased by 4.2-fold following a single hyperthermia-evoked seizure, persisting for days to a week without altering the kinetics of individual events. Combined video image and electromyogram analyses revealed that a single interictal SD is associated with prodromal motor activation followed by minutes-lasting immobility upon invasion of frontal cortex. Similar behavioral sequelae also appeared during postictal SD. Memantine treatment was effective in preventing SD exacerbation when given before and after the hyperthermic seizure, suggesting chronic activation of NMDA-receptor contributed to the prolonged SD aftermath. Interpretation: Our results reveal that cortical SD is a prominent electro-behavioral phenotype in this Scn1a deficient mouse model, and SD frequency is robustly sensitive to hyperthermic seizure induced mechanisms likely involving excess NMDAR signaling. The high susceptibility to SD may contribute to co-morbid pathophysiology in developmental epileptic encephalopathy.

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

Cited by 9 publications

References 69 publications

Enhanced Feedback Inhibition Due to Increased Recruitment of Somatostatin-Expressing Interneurons and Enhanced Cortical Recurrent Excitation in a Genetic Mouse Model of Migraine

Enhanced Feedback Inhibition Due to Increased Recruitment of Somatostatin-Expressing Interneurons and Enhanced Cortical Recurrent Excitation in a Genetic Mouse Model of Migraine

Anatomy and Physiology of Headache

A hyperthermic seizure unleashes a surge of spreading depolarizations inScn1adeficient mice

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