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AMPA and metabotropic excitoxicity explain subplate neuron vulnerability.

ABSTRACT: Cerebral hypoxia-ischemia results in unique patterns of injury during development owing to selective vulnerability of specific cell populations including subplate neurons. To evaluate the contribution of glutamate excitotoxicity, we studied enriched cultures of subplate neurons in comparison with cortical neurons, deriving expression profiles for glutamate receptor subunits by microarray and immunoblot. The excitotoxic potency of specific glutamate receptors was tested with selective agonists and antagonists. After 1 week in culture, subplate neurons are more sensitive to oxygen-glucose deprivation than cortical neurons, confirming in vivo observations. Subplate and cortical neurons are equally sensitive to glutamate and insensitive to NMDA. Subplate neurons are more sensitive than cortical neurons to AMPA and express twofold less GluR2. Subplate neurons express significantly more mGluR3, a receptor proposed to be protective. Despite this increased expression, group II mGluR agonists increase subplate neuron death and antagonists lessen glutamate excitotoxicity, suggesting a novel mechanism for subplate vulnerability.

SUBMITTER: Nguyen V

PROVIDER: S-EPMC2789448 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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AMPA and metabotropic excitoxicity explain subplate neuron vulnerability.

Nguyen Vien V McQuillen Patrick S PS

Neurobiology of disease 20091012 1

Cerebral hypoxia-ischemia results in unique patterns of injury during development owing to selective vulnerability of specific cell populations including subplate neurons. To evaluate the contribution of glutamate excitotoxicity, we studied enriched cultures of subplate neurons in comparison with cortical neurons, deriving expression profiles for glutamate receptor subunits by microarray and immunoblot. The excitotoxic potency of specific glutamate receptors was tested with selective agonists an ...[more]

PMID: 19822212

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Project description:We examined the expression of metabotropic glutamate (mGlu) receptors in species of fish that differ for their vulnerability to anoxic brain damage. Although expression of mGlu1a and mGlu5 receptors was similar in the brain of all species examined, expression of mGlu2/3 receptors was substantially higher in the brain of anoxia-tolerant species (i.e., the carp Carassius carassius and the goldfish Carassius auratus) than in the brain of species that are highly vulnerable to anoxic damage, such as the trouts Salmo trutta and Oncorhynchus mykiss. This difference was confirmed by measuring the mGlu2/3 receptor-mediated inhibition of forskolin-stimulated cAMP formation in slices prepared from the telencephalon of C. auratus and S. trutta. We exposed the goldfish C. auratus to water deprived of oxygen for 4 hr for the induction of hypoxic brain damage. Although the goldfish survived this treatment, the occurrence of apoptotic cell death could be demonstrated by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining and by the assessment of caspase-3 activity in different brain region. The extent of cell death was highest in the medulla oblongata, followed by the optic tectum, cerebellum, and hypothalamus. No cell death was found in the telencephalon. This regional pattern of hypoxic damage was inversely related to the expression of mGlu2/3 receptors, which was lowest in the medulla oblongata and highest in the telencephalon. Treatment of the goldfish with the brain permeant mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.) amplified anoxic damage throughout the brain and enabled the induction of cell death by anoxia in the telencephalon. In contrast, treatment of the goldfish with the mGlu2/3 receptor agonist LY379268 (0.5 or 1 mg/kg, i.p.) was highly protective against anoxic brain damage. Finally, exposure to the antagonist LY341495 (0.5 microm) greatly amplified the release of glutamate induced by hypoxia in slices prepared from the medulla oblongata and the telencephalon of the goldfish. We conclude that expression of mGlu2/3 receptors provides a major defensive mechanism against brain damage in anoxia-tolerant species.

Project description:BackgroundLong-Term Potentiation (LTP) of synapses is thought to be due in part to a change in AMPA Receptor trafficking leading to an increase in the number of AMPA Receptors at the synapse. LTP onset occurs within seconds after the induction signal. A particle-based stochastic simulation software is used to investigate the effect of Brownian diffusion of glutamate receptors on receptor incorporation into the synaptic specialisation and the time-course of LTP expression. The model of the dendritic spine includes receptors diffusing within the membrane, scaffold molecules within the synaptic specialisation capable of binding receptors and a molecular picket-fence surrounding the synaptic membrane area, all features found within the biological system.ResultsDuring simulations, receptors accumulate rapidly at the post-synaptic density (PSD) from the extra-synaptic membrane under a number of biologically observed conditions. The time of half-saturation, t1/2, defined as the time-point at which half the available scaffold proteins are occupied with receptors, is found to be 710 ms. Different scaffold distributions are shown to have little effect on this time-course. Decreasing the probability of escape of receptors from the PSD domain, thus localising receptors closer to the scaffold proteins, substantially decreases t1/2. A decrease of escape probability from 1 to 0 brings about a non-linear decrease in t1/2 from 710 ms to 390 ms. Release-location of receptors within the spine is found to affect the initial rate of receptor incorporation. We simulate three possible sources of receptors: (i) receptors distributed within the spine extra-synaptic membrane; (ii) receptors from exocytotic vesicles released to the synaptic spine; and (iii) receptors entering the spine from the dendritic shaft through the spine neck. Receptors released from exocytotic vesicles initially accumulate faster than receptors released from the other two sources. A model of glutamate release and glutamate-receptor interaction shows that newly inserted receptors make a substantial contribution to a glutamate evoked response within the observed time-frame.ConclusionsFast accumulation of AMPA Receptors is consistent with experimentally observed fast onset of LTP expression.

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AMPA and metabotropic excitoxicity explain subplate neuron vulnerability.

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AMPA and metabotropic excitoxicity explain subplate neuron vulnerability.

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