Glia and central cardiorespiratory pathology

Cohen, E. Myfanwy; Farnham, Melissa M.J.; Kakall, Zohra M.; Kim, Seung Jae; Nedoboy, Polina E.; Pilowsky, Paul M.

doi:10.1016/j.autneu.2018.08.003

Cited by 6 publications

(6 citation statements)

References 124 publications

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“…Neuropathology studies conducted in SUDEP are by comparison limited, but we recently observed alterations in neuropeptidergic and serotonergic neurones in the VLM in SUDEP (Patodia et al, 2018). In view of the emerging evidence of an astrogliopathy contributing to epileptogenesis (Pekny et al, 2016) as well as an hypothesised role in SIDS (Mitterauer, 2011) and the recognised physiological roles of medullary glia in respiratory regulation (Cohen et al, 2018), we speculated that medullary astrocytic populations may also be relevant in SUDEP.…”

Section: Discussionmentioning

confidence: 90%

Characterisation of medullary astrocytic populations in respiratory nuclei and alterations in sudden unexpected death in epilepsy

et al. 2019

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Central failure of respiration during a seizure is one possible mechanism for sudden unexpected death in epilepsy (SUDEP). Neuroimaging studies indicate volume loss in the medulla in SUDEP and a post mortem study has shown reduction in neuromodulatory neuropeptidergic and monoaminergic neurones in medullary respiratory nuclear groups. Specialised glial cells identified in the medulla are considered essential for normal respiratory regulation including astrocytes with pacemaker properties in the pre-Botzinger complex and populations of subpial and perivascular astrocytes, sensitive to increased pCO2, that excite respiratory neurones. Our aim was to explore niches of medullary astrocytes in SUDEP cases compared to controls. In 48 brainstems from three groups, SUDEP (20), epilepsy controls (10) and non-epilepsy controls (18), sections through the medulla were labelled for GFAP, vimentin and functional markers, astrocytic gap junction protein connexin43 (Cx43) and adenosine A1 receptor (A1R). Regions including the ventro-lateral medulla (VLM; for the pre-Bötzinger complex), Median Raphe (MR) and lateral medullary subpial layer (MSPL) were quantified using image analysis for glial cell populations and compared between groups. Findings included morphologically and regionally distinct vimentin/Cx34-positive glial cells in the VLM and MR in close proximity to neurones. We noted a reduction of vimentin-positive glia in the VLM and MSPL and Cx43 glia in the MR in SUDEP cases compared to control groups (p<0.05 to 0.005). In addition, we identified vimentin, Cx43 and A1R positive glial cells in the MSPL region which likely correspond to chemosensory glia identified experimentally. In conclusion, altered medullary glial cell populations could contribute to impaired respiratory regulatory capacity and vulnerability to SUDEP and warrant further investigation.

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Section: Discussionmentioning

confidence: 90%

Characterisation of medullary astrocytic populations in respiratory nuclei and alterations in sudden unexpected death in epilepsy

et al. 2019

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“…Although we found no changes in microglial ramification in the NTS region, these findings are not enough to rule out the possibility of an increase in the microglial activity triggered by SH. There is evidence that these cells have a high mobility and ability to change their morphology quickly (Cohen et al 2018). Previous studies showed that depending on the situation, microglia may acquire the 'alert microglia' phenotype, a state in which these cells are more activated than in their basal condition, but are not yet fully activated as in their amoeboid state; in this case, even if activated, these microglia cells may present a morphology quite similar to surveillance microglia (Hanisch & Kettenmann, 2007;Kettenmann et al 2011;Kapoor et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, increased expression of inflammatory markers after hypoxia has been documented in the systemic circulation as well in the CNS of humans and rats (Kubo et al 1998;Hartmann et al 2000;Iturriaga et al 2015). In this context, there is evidence that hypoxia triggers neuroinflammation by mechanisms related to the release of proinflammatory cytokines by microglial cells (Deng et al 2008;Kaur et al 2010;Kiernan et al 2016;Cohen et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of excitatory transmission in NTS neurons projecting to ventral medulla of rats exposed to sustained hypoxia is blunted by minocycline

Lima‐Silveira

Accorsi‐Mendonça

Bonagamba

et al. 2019

The Journal of Physiology

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Key points Rats subjected to sustained hypoxia (SH) present increases in arterial pressure (AP) and in glutamatergic transmission in the nucleus tractus solitarius (NTS) neurons sending projections to ventrolateral medulla (VLM). Treatment with minocycline, a microglial inhibitor, attenuated the increase in AP in response to SH. The increase in the amplitude of glutamatergic postsynaptic currents in the NTS‐VLM neurons, induced by postsynaptic mechanisms, was blunted by minocycline treatment. The number of microglial cells was increased in the NTS of vehicle‐treated SH rats but not in the NTS of minocycline‐treated rats. The data show that microglial recruitment/proliferation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS‐VLM neurons, which may contribute to the observed increase in AP. Abstract Short‐term sustained hypoxia (SH) produces significant autonomic and respiratory adjustments and triggers activation of microglia, the resident immune cells in the brain. SH also enhances glutamatergic neurotransmission in the NTS. Here we evaluated the role of microglial activation induced by SH on the cardiovascular changes and mainly on glutamatergic neurotransmission in NTS neurons sending projections to the ventrolateral medulla (NTS‐VLM), using a microglia inhibitor (minocycline). Direct measurement of arterial pressure (AP) in freely moving rats showed that SH (24 h, fraction of inspired oxygen (FI,O2) 0.1) in vehicle and minocycline (30 mg/kg i.p. for 3 days)‐treated groups produced a significant increase in AP in relation to control groups under normoxic conditions, but this increase was significantly lower in minocycline‐treated rats. Whole‐cell patch‐clamp recordings revealed that the active properties of the membrane were comparable among the groups. Nevertheless, the amplitudes of glutamatergic postsynaptic currents, evoked by tractus solitarius stimulation, were increased in NTS‐VLM neurons of SH rats. Changes in asynchronous glutamatergic currents indicated that the observed increase in amplitude was due to postsynaptic mechanisms. These changes were blunted in the SH group previously treated with minocycline. Using immunofluorescence, we found that the number of microglial cells was increased in the NTS of vehicle‐treated SH rats but not in the NTS neurons of minocycline‐treated rats. Our data support the concept that microglial activation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS‐VLM neurons, which may contribute to the increase in AP observed in this experimental model.

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“…The putative role of microglia in augmenting hypoxic ventilation is akin to the presumptive role of astrocytes in hypoxia sensing by the brain tissue [9][10][11][12][13][14][15][16][17][18][19]. It has been reported that activated microglia release ATP that stimulates astrocytic purinergic receptors and increases the excitatory postsynaptic current frequency in neurons through a metabotropic glutamate receptor mechanism [52].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies focused mainly on neurons, regarding the cellular mechanisms of central hypoxic cardiorespiratory regulation [5][6][7][8]. In recent years, the involvement of glial cells, particularly astrocytes, in the hypoxic regulation of cardiorespiratory function has attracted attention [9][10][11][12][13][14][15][16][17][18][19]. Microglia, another type of glial cells, are known to evoke pro/antiinflammatory responses in the central nervous system and contribute to synaptic plasticity [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Role of microglia in blood pressure and respiratory responses to acute hypoxic exposure in rats

et al. 2022

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Microglia modulate cardiorespiratory activities during chronic hypoxia. It has not been clarified whether microglia are involved in the cardiorespiratory responses to acute hypoxia. Here we investigated this issue by comparing cardiorespiratory responses to two levels of acute hypoxia (13% O2 for 4 min and 7% O2 for 5 min) in conscious unrestrained rats before and after systemic injection of minocycline (MINO), an inhibitor of microglia activation. MINO increased blood pressure but not lung ventilation in the control normoxic condition. Acute hypoxia stimulated cardiorespiratory responses in MINO-untreated rats. MINO failed to significantly affect the magnitude of hypoxia-induced blood pressure elevation. In contrast, MINO tended to suppress the ventilatory responses to hypoxia. We conclude that microglia differentially affect cardiorespiratory regulation depending on the level of blood oxygenation. Microglia suppressively contribute to blood pressure regulation in normoxia but help maintain ventilatory augmentation in hypoxia, which underscores the dichotomy of central regulatory pathways for both systems.

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Glia and central cardiorespiratory pathology

Cited by 6 publications

References 124 publications

Characterisation of medullary astrocytic populations in respiratory nuclei and alterations in sudden unexpected death in epilepsy

Characterisation of medullary astrocytic populations in respiratory nuclei and alterations in sudden unexpected death in epilepsy

Enhancement of excitatory transmission in NTS neurons projecting to ventral medulla of rats exposed to sustained hypoxia is blunted by minocycline

Role of microglia in blood pressure and respiratory responses to acute hypoxic exposure in rats

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