Domoic acid suppresses hyperexcitation in the network due to activation of kainate receptors of GABAergic neurons

Kosenkov, Artem M.; Teplov, Ilia Y.; Сергеев, А. И.; Maiorov, S. A.; Зинченко, В. П.; Gaidin, Sergei G.

doi:10.1016/j.abb.2019.06.004

Cited by 21 publications

(16 citation statements)

References 61 publications

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“…For identification of cell types (neurons and astrocytes), cell cultures were stained with antibodies against the glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN) after vital [Ca 2+ ] i imaging. The detailed protocol of immunostaining was described previously (Kosenkov et al, ; Turovskaya, Gaidin, Mal'tseva, Zinchenko, & Turovsky, ). Briefly, the cell cultures were washed three times with 10 mM PBS after the experiments and incubated for 20 min with 4% PFA.…”

Section: Methodsmentioning

confidence: 99%

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Gaidin

Зинченко

Сергеев

et al. 2019

Glia

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Norepinephrine is one of the key neurotransmitters in the hippocampus, but its role in the functioning of the neuroglial networks remains unclear. Here we show that norepinephrine suppresses NH4Cl‐induced oscillations of the intracellular Ca2+ concentration ([Ca2+]i) in hippocampal neurons. We found that the inhibitory effect of norepinephrine against ammonium‐induced [Ca2+]i oscillations is mediated by activation of alpha‐2 adrenergic receptors. Furthermore, UK 14,304, an agonist of alpha‐2 adrenergic receptors, evokes a biphasic [Ca2+]i elevation in a minor population of astrocytes. This elevation consists of an initial fast, peak‐shaped [Ca2+]i rise, mediated by Giβγ subunit and subsequent PLC‐induced mobilization of Ca2+ from internal stores, and a plateau phase, mediated by a Ca2+ influx from the extracellular medium through store‐operated and TRPC3 channels. We show the correlation between the Ca2+ response in astrocytes and suppression of [Ca2+]i oscillations in neurons. The inhibitory effect of UK 14,304 is abolished in the presence of gallein, an inhibitor of Gβγ‐signaling. In turn, application of the agonist in the presence of the PLC inhibitor decreases the frequency and amplitude of [Ca2+]i oscillations in neurons but does not suppress them. The same effect is observed in the presence of bicuculline, a GABA(A) receptor antagonist. We demonstrate that UK 14,304 application increases the frequency and amplitude of slow outward chloride currents in neurons, indicating the release of GABA by astrocytes. Thus, our findings indicate that the activation of astrocytic alpha‐2 adrenergic receptors stimulates GABA release from astrocytes via Giβγ subunit‐associated signaling pathway, contributing to the suppression of neuronal activity.

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Section: Methodsmentioning

confidence: 99%

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Gaidin

Зинченко

Сергеев

et al. 2019

Glia

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“…1 A). It is known that GAD65/67 is expressed exclusively in neurons [ 29 ]. The Ca 2+ responses of GABAergic and glutamatergic neurons to brief applications of NMDA (10 μmol/L in Mg 2+ -free medium), a selective agonist of NMDARs, were found to decrease after hypoxia/reoxygenation cycles (Fig.…”

Section: Resultsmentioning

confidence: 99%

BDNF Overexpression Enhances the Preconditioning Effect of Brief Episodes of Hypoxia, Promoting Survival of GABAergic Neurons

et al. 2020

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Hypoxia causes depression of synaptic plasticity, hyperexcitation of neuronal networks, and the death of specific populations of neurons. However, brief episodes of hypoxia can promote the adaptation of cells. Hypoxic preconditioning is well manifested in glutamatergic neurons, while this adaptive mechanism is virtually suppressed in GABAergic neurons. Here, we show that brain-derived neurotrophic factor (BDNF) overexpression in neurons enhances the preconditioning effect of brief episodes of hypoxia. The amplitudes of the NMDAR-and AMPARmediated Ca 2? responses of glutamatergic and GABAergic neurons gradually decreased after repetitive brief hypoxia/ reoxygenation cycles in cell cultures transduced with the (AAV)-Syn-BDNF-EGFP virus construct. In contrast, the amplitudes of the responses of GABAergic neurons increased in non-transduced cultures after preconditioning. The decrease of the amplitudes in GABAergic neurons indicated the activation of mechanisms of hypoxic preconditioning. Preconditioning suppressed apoptotic or necrotic cell death. This effect was most pronounced in cultures with BDNF overexpression. Knockdown of BDNF abolished the effect of preconditioning and promoted the death of GABAergic neurons. Moreover, the expression of the anti-apoptotic genes Stat3, Socs3, and Bcl-xl substantially increased 24 h after hypoxic episodes in the transduced cultures compared to controls. The expression of genes encoding the pro-inflammatory cytokines IL-10 and IL-6 also increased. In turn, the expression of pro-apoptotic (Bax, Casp-3, and Fas) and proinflammatory (IL-1b and TNFa) genes decreased after hypoxic episodes in cultures with BDNF overexpression. Inhibition of vesicular BDNF release abolished its protective action targeting inhibition of the oxygen-glucose deprivation (OGD)-induced [Ca 2? ] i increase in GABAergic and glutamatergic neurons, thus promoting their death. Bafilomycin A1, Brefeldin A, and tetanus toxin suppressed vesicular release (including BDNF) and shifted the gene expression profile towards excitotoxicity, inflammation, and apoptosis. These inhibitors of vesicular release abolished the protective effects of hypoxic preconditioning in glutamatergic neurons 24 h after hypoxia/reoxygenation cycles. This finding indicates a significant contribution of vesicular BDNF release to the development of the mechanisms of hypoxic preconditioning. Thus, our results demonstrate that BDNF plays a pivotal role in the activation and enhancement of the preconditioning effect of brief episodes of hypoxia and promotes tolerance of the most vulnerable populations of GABAergic neurons to hypoxia/ischemia.

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“…The seizures are likely to be caused by a variety of mechanisms, including specific and non-specific immunity, neuronal damage, and ischemia ( 4 , 7 , 8 ). It is still a matter of debate, whether epilepsy may be the only clinical manifestation of autoimmune encephalitis or whether immune-mediated mechanisms may contribute to development of seizures following previous structural damage to the brain ( 1 , 2 , 16 , 17 ). The design of our preliminary study (especially the structure of the studied subgroups) was meant to address the above theories.…”

Section: Discussionmentioning

confidence: 99%

Occult Autoimmune Background for Epilepsy—The Preliminary Study on Antibodies Against Neuronal Surface Antigens

Dziadkowiak

Moreira

Buska-Mach³

et al. 2021

Front. Neurol.

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Objective: The objective of the study was to determine the incidence of antibodies against neuronal surface antigens (NSA-ab) in patients with different types of epilepsy, in comparison with the subjects diagnosed with immune-mediated disorders.Methods: Forty patients with drug-resistant epilepsy (DRE) of unknown origin, 16 with post-stroke epilepsy, and 23 with systemic autoimmune disorders (SAD) with CNS involvement were included. NSA-ab were sought in serum using indirect immunofluorescence method. Relationships were analyzed between presence of NSA-ab and clinical presentation.Results: NSA-ab was detected in the sera from five patients: anti-DPPX in one patient, anti-AMPAR1/R2 in two, anti-LGI1 in one and, in one case, both anti-CASPR2 and DPPX IgG. Out of these five patients, three represented the SAD subgroup and two the DRE subgroup. None of the patients with post-stroke epilepsy was positive for NSA-ab.Significance: Autoimmune etiology is worth considering in patients with drug-resistant epilepsy of unknown origin. The presence of NSA-ab in patients with systemic autoimmune disorders may be caused by unspecifically enhanced autoimmune reactivity. NSA-ab seem not to be related to epilepsy resulting from ischemic brain injury.

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Domoic acid suppresses hyperexcitation in the network due to activation of kainate receptors of GABAergic neurons

Cited by 21 publications

References 61 publications

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

Activation of alpha‐2 adrenergic receptors stimulates GABA release by astrocytes

BDNF Overexpression Enhances the Preconditioning Effect of Brief Episodes of Hypoxia, Promoting Survival of GABAergic Neurons

Occult Autoimmune Background for Epilepsy—The Preliminary Study on Antibodies Against Neuronal Surface Antigens

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