Hypoxia-induced depression of synaptic transmission becomes irreversible by intracellular accumulation of non-excitatory amino acids

Álvarez-Merz, Iris; Luengo, Javier G.; Muñoz, Marı́a-Dolores; Hernández‐Guijo, Jesús M.; Solís, José M.

doi:10.1016/j.neuropharm.2021.108557

Cited by 6 publications

(15 citation statements)

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“…Previously we showed that inhibition of NMDAR rescued the irreversible loss of synaptic potentials induced by a combination of seven non-excitatory AA (AGHQSTU) during hypoxia (Álvarez-Merz et al, 2021). Here, we demonstrated that inhibition of NMDAR during hypoxia with AGQS stopped neuronal soma swelling and dendritic beading without preventing the increase in astroglial soma volume.…”

Section: Discussionmentioning

confidence: 99%

“…System A and N are mainly expressed in neurons and astrocytes, respectively (Bröer, 2014; Rubio-Aliaga and Wagner, 2016). However, inhibition of system A in normoxic slices didn’t prevent cellular swelling and tissue accumulation of AA as assessed with electrophysiology and HPLC (Álvarez-Merz et al, 2021). Future studies are necessary to evaluate the involvement of system N. Although GPNA is frequently used as an ASCT2 inhibitor, it is not entirely specific and could also affect systems A and N (Bröer et al, 2016), complicating data interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…Cellular swelling can be indirectly measured by increased extracellular resistance (Chebabo et al, 1995) and field potential amplitude (Rosen and Andrew, 1990). Accordingly, we have shown that the intracellular accumulation of a mixture of seven non-excitatory AA (L-alanine, glycine, L-histidine, L-glutamine, L-serine, L-threonine, and taurine, abbreviated as one letter code: AGHQSTU) applied to hippocampal slices at their plasmatic concentrations induces synaptic potentiation suggesting cell swelling (Álvarez-Merz et al, 2021). Most of these AA are substrates of several Na + -dependent AA transporter systems located in the neuronal and astroglial plasma membrane, such as systems A and N (SLC38 family) (Bröer, 2014) and alanine-serine-cysteine transporters (ASCT; SLC1 family) (Bröer et al, 1999; Weiss et al, 2001; Gliddon et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Most of these AA are substrates of several Na + -dependent AA transporter systems located in the neuronal and astroglial plasma membrane, such as systems A and N (SLC38 family) (Bröer, 2014) and alanine-serine-cysteine transporters (ASCT; SLC1 family) (Bröer et al, 1999;Weiss et al, 2001;Gliddon et al, 2009). However, pharmacological inhibition of system A transport did not prevent synaptic potentiation induced by the AGHQSTU mixture (Álvarez-Merz et al, 2021), indicating that system A alone is insufficient for intracellular accumulation of AA observed in this study.…”

Section: Introductionmentioning

confidence: 99%

“…The release of excitatory AA by activated VRAC was proposed to aggravate excitotoxicity and induce neuronal damage in metabolically compromised tissue (Wilson et al, 2019). Indeed, we have shown that the reversible loss of synaptic transmission induced by hypoxia turns irreversible by non-excitatory AA and involves NMDA receptor (NMDAR) activation (Álvarez-Merz et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Álvarez-Merz

Fomitcheva

Sword

et al. 2022

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Bleeding into cerebral parenchyma during hemorrhagic stroke or head trauma leads to ischemia and release of plasmatic content, including amino acids (AA). Although excitotoxic AA have been extensively studied, little is known about non-excitatory AA during hypoxic injury. Hypoxia-induced synaptic depression becomes irreversible after adding non-excitatory AA to hippocampal slices, alongside their intracellular accumulation and increased tissue electrical resistance. A combination of four non-excitatory AA (L-alanine, glycine, L-glutamine, L-serine: AGQS) at plasmatic concentrations was applied to brain slices from transgenic mice expressing EGFP in pyramidal neurons or astrocytes during normoxia or hypoxia. Two-photon imaging, changes in light transmittance (LT), and electrophysiological field recordings followed by electron microscopy in hippocampal CA1 st. radiatum were used to monitor synaptic function concurrently with cellular swelling and injury. During normoxia, AGQS-induced increase in LT was due to astroglial but not neuronal swelling. Fast LT raise during hypoxia and AGQS manifested neuronal and astroglial swelling accompanied by a permanent loss of synaptic transmission and irreversible dendritic beading, signifying acute tissue damage. Neuronal injury was not triggered by spreading depolarization which did not occur in our experiments. Hypoxia without AGQS did not cause cell swelling, leaving dendrites intact. Inhibition of NMDA receptors prevented neuronal damage and irreversible loss of synaptic function. Deleterious effects of AGQS during hypoxia were prevented by alanine-serine-cysteine transporters (ASCT2) and volume-regulated anion channels (VRAC) blockers. Our findings suggest that swelling induced by intracellular accumulation of non-excitatory AA and release of excitotoxins through antiporters and VRAC may exacerbate the hypoxia-induced neuronal injury.Significance StatementLittle is known if non-excitatory amino acids (AA) contribute to cellular injury when released during bleeding, as in hemorrhagic stroke and head trauma. Alanine, glycine, glutamine, and serine are one of the most abundant in plasma. Remarkably, during hypoxia, these non-excitatory AA caused severe neuronal and astroglial swelling and irreversible dendritic injury alongside a permanent loss of synaptic function. Activation of NMDA receptors was implicated in the onset of damage. Experimental evidence pointed to the involvement of alanine-serine-cysteine transporter 2 (ASCT2) and volume-regulated anion channels (VRAC) as molecular mechanisms underlying AA-induced damage during hypoxia. A detailed understanding of how brain injury evolves with non-excitatory AA during hypoxia will help design brain recovery treatments in neurological conditions involving bleeding.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Álvarez-Merz

Fomitcheva

Sword

et al. 2022

Preprint

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Novel mechanism of hypoxic neuronal injury mediated by non‐excitatory amino acids and astroglial swelling

Álvarez-Merz

Fomitcheva

Sword

et al. 2022

Glia

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In ischemic stroke and post-traumatic brain injury (TBI), blood-brain barrier disruption leads to leaking plasma amino acids (AA) into cerebral parenchyma. Bleeding in hemorrhagic stroke and TBI also release plasma AA. Although excitotoxic AA were extensively studied, little is known about non-excitatory AA during hypoxic injury.Hypoxia-induced synaptic depression in hippocampal slices becomes irreversible with non-excitatory AA, alongside their intracellular accumulation and increased tissue electrical resistance. Four non-excitatory AA (L-alanine, glycine, L-glutamine, L-serine: AGQS) at plasmatic concentrations were applied to slices from mice expressing EGFP in pyramidal neurons or astrocytes during normoxia or hypoxia. Two-photon imaging, light transmittance (LT) changes, and electrophysiological field recordings followed by electron microscopy in hippocampal CA1 st. radiatum were used to monitor synaptic function concurrently with cellular swelling and injury. During normoxia, AGQSinduced increase in LT was due to astroglial but not neuronal swelling. LT raise during hypoxia and AGQS manifested astroglial and neuronal swelling accompanied by a permanent loss of synaptic transmission and irreversible dendritic beading, signifying acute damage. Neuronal injury was not triggered by spreading depolarization which did not occur in our experiments. Hypoxia without AGQS did not cause cell swelling, leaving dendrites intact. Inhibition of NMDA receptors prevented neuronal damage and irreversible loss of synaptic function. Deleterious effects of AGQS during hypoxia were prevented by alanine-serine-cysteine transporters (ASCT2) and volumeregulated anion channels (VRAC) blockers. Our findings suggest that astroglial swelling induced by accumulation of non-excitatory AA and release of excitotoxins through antiporters and VRAC may exacerbate the hypoxia-induced neuronal injury.

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Identification of Non-excitatory Amino Acids and Transporters Mediating the Irreversible Synaptic Silencing After Hypoxia

Álvarez-Merz,

Muñoz,

Hernández-Guijo

et al. 2023

Transl. Stroke Res.

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Hypoxia-induced depression of synaptic transmission becomes irreversible by intracellular accumulation of non-excitatory amino acids

Cited by 6 publications

References 61 publications

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling

Novel mechanism of hypoxic neuronal injury mediated by non‐excitatory amino acids and astroglial swelling

Identification of Non-excitatory Amino Acids and Transporters Mediating the Irreversible Synaptic Silencing After Hypoxia

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