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Age dependent changes in synaptic NMDA receptor composition in adult human cortical neurons

Age dependent changes in synaptic NMDA receptor composition in adult human cortical neurons
Age dependent changes in synaptic NMDA receptor composition in adult human cortical neurons
The molecular processes underlying the ageing-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown that N-methyl-D-aspartate receptors (NMDARs) containing GluN2B subunits can enhance the ability of synapses to undergo long term potentiation. In ageing rodents, the contribution of GluN2B to synaptic function is reduced compared to younger animals and the decline in GluN2B subunit expression is correlated with impaired memory functions. However, the contribution of GluN2B containing receptors to synaptic transmission in cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B containing NMDARs in adult human neurons using fresh non-pathological 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.
NR2A, NR2B, human, resected, surgical
1047-3211
4246-4256
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Pegasiou, Chrysia-Maria
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Zolnourian, Ardalan
5e8d4881-cdfd-4cb1-8eae-b98b13104648
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Ahmed, Aminul
175a1358-5255-4f20-8cf9-96fac237bc9f
Vajramani, Girish V.
c3065130-3c48-45fb-b771-299ed0c66fa9
Grundy, Paul
0ceddba7-59f8-469f-8b50-4d08936e92a0
Verhoog, Matthijs
bcd28eee-05b2-4a4d-980a-893d969b5530
Mansvelder, Huibert
fa35a895-4305-4709-90c5-62b155047ecf
Perry, V. Hugh
1cfaa2eb-cd6c-439e-9db3-b4258f3235e6
Bulters, Diederik
f2080cef-122a-486d-925d-455316b8cd41
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Pegasiou, Chrysia-Maria
70534d16-7533-40c3-b017-2840366f6618
Zolnourian, Ardalan
5e8d4881-cdfd-4cb1-8eae-b98b13104648
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Ahmed, Aminul
175a1358-5255-4f20-8cf9-96fac237bc9f
Vajramani, Girish V.
c3065130-3c48-45fb-b771-299ed0c66fa9
Grundy, Paul
0ceddba7-59f8-469f-8b50-4d08936e92a0
Verhoog, Matthijs
bcd28eee-05b2-4a4d-980a-893d969b5530
Mansvelder, Huibert
fa35a895-4305-4709-90c5-62b155047ecf
Perry, V. Hugh
1cfaa2eb-cd6c-439e-9db3-b4258f3235e6
Bulters, Diederik
f2080cef-122a-486d-925d-455316b8cd41

Vargas-Caballero, Mariana, Pegasiou, Chrysia-Maria, Zolnourian, Ardalan, Gomez-Nicola, Diego, Deinhardt, Katrin, Nicoll, James, Ahmed, Aminul, Vajramani, Girish V., Grundy, Paul, Verhoog, Matthijs, Mansvelder, Huibert, Perry, V. Hugh and Bulters, Diederik (2020) Age dependent changes in synaptic NMDA receptor composition in adult human cortical neurons. Cerebral Cortex, 30 (7), 4246-4256, [bhaa052]. (doi:10.1093/cercor/bhaa052).

Record type: Article

Abstract

The molecular processes underlying the ageing-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown that N-methyl-D-aspartate receptors (NMDARs) containing GluN2B subunits can enhance the ability of synapses to undergo long term potentiation. In ageing rodents, the contribution of GluN2B to synaptic function is reduced compared to younger animals and the decline in GluN2B subunit expression is correlated with impaired memory functions. However, the contribution of GluN2B containing receptors to synaptic transmission in cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B containing NMDARs in adult human neurons using fresh non-pathological 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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Age dependent changes in synaptic NMDA - Accepted Manuscript
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Accepted/In Press date: 7 February 2020
Published date: 17 March 2020
Keywords: NR2A, NR2B, human, resected, surgical

Identifiers

Local EPrints ID: 438981
URI: http://eprints.soton.ac.uk/id/eprint/438981
ISSN: 1047-3211
PURE UUID: 456f2ba6-ff99-4b0e-ad7c-73ba5e599a03
ORCID for Mariana Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 31 Mar 2020 16:30
Last modified: 18 Feb 2021 17:20

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Contributors

Author: Chrysia-Maria Pegasiou
Author: Ardalan Zolnourian
Author: James Nicoll ORCID iD
Author: Aminul Ahmed
Author: Girish V. Vajramani
Author: Paul Grundy
Author: Matthijs Verhoog
Author: Huibert Mansvelder
Author: V. Hugh Perry
Author: Diederik Bulters

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