Effects of glycine antagonists in an acute in vitro electrophysiological model of ischemia

Schilp, Donald E.; Sorensen, Stephen M.; Wettstein, Joseph G.; Black, Mark D.

doi:10.1002/(sici)1098-2299(199902)46:2<134::aid-ddr6>3.0.co;2-9

Cited by 3 publications

(1 citation statement)

References 23 publications

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“…MK801, which is a non-competitive channel blocker whose washout is at least partially dependent on channel opening (McKay et al, 2013 ), might provide greater protection than APV because of incomplete washout during the recording period. Other examples of protection of hippocampal slices against excitotoxicity by MK801 but not APV have been reported (Schurr et al, 1995a , b ; Schilp et al, 1999 ; Pringle et al, 2000 ), as well as a recent observation that MK801, but not APV, downregulates the expression of misfolded isoforms (PrP Sc ) of cellular prior protein (PrP C ; Zattoni et al, 2021 ).…”

Section: Discussionmentioning

confidence: 94%

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Rimmele

Andersen

et al. 2021

Front. Cell. Neurosci.

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GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20–25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.

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Section: Discussionmentioning

confidence: 94%

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Rimmele

Andersen

et al. 2021

Front. Cell. Neurosci.

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Radiosynthesis of a ligand for studying the glycine transporter: [¹¹C]ALX‐5407

Ravert

Mathews

Klitenick³

et al. 2001

Labelled Comp Radiopharmac

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Abstract[11C]ALX‐5407, R‐N[3‐(4′‐fluorophenyl)‐3‐(4′‐phenylphenoxy)propyl] sarcosine, a chiral glycine transporter 1 antagonist, was labeled with [11C]iodomethane by N‐alkylation of methyl ester protected N‐normethyl precursor, ALX‐5536, and subsequent saponification of the methyl ester protecting group. The time for synthesis, purification, and formulation was 33 minutes with an average specific radioactivity of 3909 mCi/µmol (EOS) and average decay corrected radiochemical yield of 8%. Copyright © 2001 John Wiley & Sons, Ltd.

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Effect of AMPA receptor modulators on hippocampal and cortical function

Black

Wotanis

Schilp

et al. 2000

European Journal of Pharmacology

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Effects of glycine antagonists in an acute in vitro electrophysiological model of ischemia

Cited by 3 publications

References 23 publications

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Radiosynthesis of a ligand for studying the glycine transporter: [¹¹C]ALX‐5407

Effect of AMPA receptor modulators on hippocampal and cortical function

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Effects of glycine antagonists in an acute in vitro electrophysiological model of ischemia

Cited by 3 publications

References 23 publications

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus

Radiosynthesis of a ligand for studying the glycine transporter: [11C]ALX‐5407

Effect of AMPA receptor modulators on hippocampal and cortical function

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Product

Resources

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Radiosynthesis of a ligand for studying the glycine transporter: [¹¹C]ALX‐5407