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. 2000 Sep;2(3):219-32.

NMDA Receptor Function, Memory, and Brain Aging

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Free PMC article

NMDA Receptor Function, Memory, and Brain Aging

J W Newcomer et al. Dialogues Clin Neurosci. .
Free PMC article

Abstract

An increasing level of N-methyl-D-aspartate (NMDA) receptor hypofunction within the brain is associated with memory and learning impairments, with psychosis, and ultimately with excitotoxic brain injury. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, contributing to decreases in memory and learning performance. In those individuals destined to develop Alzheimer's disease, other abnormalities (eg, amyloidopathy and oxidative stress) interact to increase the NMDA receptor hypofunction (NRHypo) burden. In these vulnerable individuals, the brain then enters into a severe and persistent NRHypo state, which can lead to widespread neurodegeneration with accompanying mental symptoms and further cognitive deterioration. If the hypotheses described herein prove correct, treatment implications may be considerable. Pharmacological methods for preventing the overstimulation of vulnerable corticolimbic pyramidal neurons developed in an animal model may be applicable to the prevention and treatment of Alzheimer's disease.

La acentuación de la hipofunción del receptor N-metil-D-aspartato (NMDA) en el cerebro se ha asociado con deterioro en la memoria y el aprendizaje, con psicosis y, últimamente con daño exitotóxico. Así como el cerebro envejece, el sistema de receptores NMDA progresivamente se torna hipofuncional, lo que contribuye a una disminución de los rendimientos de memoria y aprendizaje. En aquellos individuos vulnerables para desarrollar la enfermedad de Alzheimer hay otras anormalidades (como amiloidopatías y el estrés oxidativo) que interactúan para aumentar la carga de la hipofunción del receptor NMDA. En estos individuos vulnerables, el cerebro entra en un severo y persistente estado de hipofunción del receptor NMDA, el cual puede conducir a una neurodegeneracíon generalizada, con síntomas mentales asociados y a un posterior deterioro cognitivo. Si se demuestra que la hipótesis descrita previamente es correcta, las implicancias terapéuticas de ella pueden ser considerables. Los métodos farmacológicos para prevenir la sobreestimulación de neuronas piramidales córtico-límbicas vulnerables desarrolladas en un modelo animal pueden ser aplicables a la prevención y al tratamiento de la enfermedad de Alzheimer.

L'augmentation de l'hypofonctionnement des récepteurs du N-méthyl-D-aspartate (NMDA) dans le cerveau est associée à des troubles de la mémoire et de l'apprentissage, qui s'accompagnent de psychose et évoluent vers des lésions cérébrales excitotoxiques. Lors du vieillissement cérébral, le système des récepteurs du NMDA devient progressivement hypofonctionnel, contribuant à la diminution des performances mnésiques et d'apprentissage. Chez les individus prédisposés à développer une maladie d'Alzheimer (MA), d'autres anomalies (telles que les amyloïdopathies et le stress oxydatif) interagissent pour augmenter le degré d'hypofonctionnement (NRHypo) des récepteurs du NMDA. Chez ces individus fragiles, le cerveau s'installe alors dans un état d'hypofonctionnement permanent et sévère qui peut conduire à une neurodégénération étendue associée à des symptômes mentaux et d'autres détériorations cognitives. Si les hypothèses décrites ici s'avèrent exactes, les implications thérapeutiques pourraient être considérables. Les méthodes pharmacologiques de prévention de l'hyperstimulation des neurones corticolimbiques vulnérables, développées dans des modèles animaux, pourraient s'appliquer à la prévention et au traitement de la maladie d'Alzheimer.

Keywords: Alzheimer's disease; NMDA receptor; NMDA receptor hypofunction; brain aging; memory.

Figures

Figure 1.
Figure 1.. To explain NMDA receptor hypofunction (NRHypo)-induced neurotoxicity of posterior cingulate and retrosplenial (PC/RS) neurons, we propose that Glu acting through NMDA receptors on GABAergic, serotonergic, and noradrenergic neurons maintain tonic inhibitory control over multiple excitatory pathways that convergently innervate PC/RS neurons. Systemic administration of an NMDA receptor antagonist (or NRHypo produced by any mechanism) would simultaneously abolish inhibitory control over multiple excitatory inputs to PC/RS neurons. This would create chaotic disruption among multiple intracellular second messenger systems, thereby causing derangement of cognitive functions subserved by the afflicted neurons, as well as eventual degeneration of these neurons. This circuit diagram focuses exclusively on PC/RS neurons. However, we hypothesize that a similar disinhibition mechanism and similar but not necessarily identical neural circuits and receptor mechanisms mediate damage induced in other corticolimbic brain regions by sustained NRHypo. (+): excitatory input; (-): inhibitory input; Ach: acetylcholine; NE: norepinephrine; σ: sigma binding site; 5-HT: serotonin; α2; α2 subtype of the adrenergic receptor; GA: GABAA subtype of the GABA receptor; M3: M3 subtype of the muscarinic cholinergic receptor; non-NMDA: non-NMDA subtype of the Glu ionotropic receptor; NMDA: NMDA subtype of the Glu receptor; 5-HT2A: 5-HT2A subtype of the 5-HT receptor.

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References

    1. Olney JW. Excitotoxic amino acids and neuropsychiatrie disorders. Annu Rev Pharmacol Toxicol. 1990;30:47–71. - PubMed
    1. Choi DW. Excitotoxic cell death. J Neurobiol. 1992;23:1261–1276. - PubMed
    1. Rothstein JD., Van Kammen M., LeveyAI, Martin LJ., Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotropic lateral sclerosis. Ann Neurol. 1995;38:73–84. - PubMed
    1. Ikonomidou C., Qin YQ., Labruyere J., Olney JW. Motor neuron degeneration induced by excitotoxin agonists has features in common with that seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1996;55:211–224. - PubMed
    1. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–634. - PubMed

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