Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons

Chrysia M. Pegasiou; Ardalan Zolnourian; Diego Gomez-Nicola; Katrin Deinhardt; James A.R. Nicoll; Aminul I. Ahmed; Girish Vajramani; Paul Grundy; Matthijs B. Verhoog; Huibert D. Mansvelder; V. H. Perry; Diederik Bulters; Mariana Vargas-Caballero

doi:10.1093/cercor/bhaa052

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons

Chrysia M. Pegasiou, Ardalan Zolnourian, Diego Gomez-Nicola, Katrin Deinhardt, James A.R. Nicoll, Aminul I. Ahmed, Girish Vajramani, Paul Grundy, Matthijs B. Verhoog, Huibert D. Mansvelder, V. H. Perry, Diederik Bulters, Mariana Vargas-Caballero

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Abstract

The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

Original language	English
Pages (from-to)	4246-4256
Number of pages	11
Journal	Cerebral cortex (New York, N.Y. : 1991)
Volume	30
Issue number	7
Early online date	17 Mar 2020
DOIs	https://doi.org/10.1093/cercor/bhaa052
Publication status	Published - Jul 2020

Funding

Institute for Life Sciences, University of Southampton (Senior Research Fellowship to M.V.C.); Wessex Medical Research (Innovation Grant to M.V.C.); Gerald Kerkut Trust (PhD studentship to C.M.P.).

Funders	Funder number
Institute for Life Sciences, University of Southampton
Gerald Kerkut Trust
Wessex Medical Research

Keywords

human
NR2A
NR2B
resected
surgical

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10.1093/cercor/bhaa052

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical NeuronsFinal published version, 1.02 MBLicence: Article 25fa Dutch Copyright Act

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Pegasiou, C. M., Zolnourian, A., Gomez-Nicola, D., Deinhardt, K., Nicoll, J. A. R., Ahmed, A. I., Vajramani, G., Grundy, P., Verhoog, M. B., Mansvelder, H. D., Perry, V. H., Bulters, D., & Vargas-Caballero, M. (2020). Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons. Cerebral cortex (New York, N.Y. : 1991), 30(7), 4246-4256. https://doi.org/10.1093/cercor/bhaa052

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abstract = "The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.",

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Pegasiou, CM, Zolnourian, A, Gomez-Nicola, D, Deinhardt, K, Nicoll, JAR, Ahmed, AI, Vajramani, G, Grundy, P, Verhoog, MB, Mansvelder, HD, Perry, VH, Bulters, D & Vargas-Caballero, M 2020, 'Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons', Cerebral cortex (New York, N.Y. : 1991), vol. 30, no. 7, pp. 4246-4256. https://doi.org/10.1093/cercor/bhaa052

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AU - Pegasiou, Chrysia M.

AU - Zolnourian, Ardalan

AU - Gomez-Nicola, Diego

AU - Deinhardt, Katrin

AU - Nicoll, James A.R.

AU - Ahmed, Aminul I.

AU - Vajramani, Girish

AU - Grundy, Paul

AU - Verhoog, Matthijs B.

AU - Mansvelder, Huibert D.

AU - Perry, V. H.

AU - Bulters, Diederik

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Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons

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