NLX-101, a 5-HT1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats

R.P. Aguiar; L.M. Soares; M. Varney; A.A. Newman-Tancredi; H. Milani; J. Prickaerts; R.M.W. de Oliveira

doi:10.1016/j.neurobiolaging.2022.12.013

NLX-101, a 5-HT1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats

R.P. Aguiar
, L.M. Soares
, M. Varney
, A.A. Newman-Tancredi
, H. Milani
, J. Prickaerts
, R.M.W. de Oliveira^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

5-HT1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT1A receptor-biased agonist, and F13714, a presynaptic 5-HT1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Un-like younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT1A as a treatment for cognitive deficits related to aging.(c) 2023 Elsevier Inc. All rights reserved.

Original language	English
Pages (from-to)	52-59
Number of pages	8
Journal	Neurobiology of Aging
Volume	124
Issue number	1
DOIs	https://doi.org/10.1016/j.neurobiolaging.2022.12.013
Publication status	Published - 1 Apr 2023

Keywords

Pattern separation
F13714
NLX-101
5-HT 1A receptor
Neuroplasticity
Aged rats
DENTATE GYRUS
HIPPOCAMPAL NEUROGENESIS
SYNAPTIC PLASTICITY
NEUROTROPHIC FACTOR
ADULT NEUROGENESIS
F15599
PROTEINS
BRAIN
COGNITION
DEFICITS

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10.1016/j.neurobiolaging.2022.12.013

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title = "NLX-101, a 5-HT1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats",

abstract = "5-HT1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT1A receptor-biased agonist, and F13714, a presynaptic 5-HT1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Un-like younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT1A as a treatment for cognitive deficits related to aging.(c) 2023 Elsevier Inc. All rights reserved.",

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author = "R.P. Aguiar and L.M. Soares and M. Varney and A.A. Newman-Tancredi and H. Milani and J. Prickaerts and \{de Oliveira\}, R.M.W.",

note = "Funding Information: The authors thank Marco Alberto Trombelli for his technical support and Britt van Hagen and Dr. Nick van Goethem for their expert advice. This study was supported by Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (CNPq) , CAPES/ NUFFIC 88887156527/2019-00 , Brazil, Universidade Estadual de Maring{\'a} and the University of Maastricht . Publisher Copyright: {\textcopyright} 2022",

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doi = "10.1016/j.neurobiolaging.2022.12.013",

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AU - Aguiar, R.P.

AU - Soares, L.M.

AU - Varney, M.

AU - Newman-Tancredi, A.A.

AU - Milani, H.

AU - Prickaerts, J.

AU - de Oliveira, R.M.W.

N1 - Funding Information: The authors thank Marco Alberto Trombelli for his technical support and Britt van Hagen and Dr. Nick van Goethem for their expert advice. This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) , CAPES/ NUFFIC 88887156527/2019-00 , Brazil, Universidade Estadual de Maringá and the University of Maastricht . Publisher Copyright: © 2022

PY - 2023/4/1

Y1 - 2023/4/1

N2 - 5-HT1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT1A receptor-biased agonist, and F13714, a presynaptic 5-HT1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Un-like younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT1A as a treatment for cognitive deficits related to aging.(c) 2023 Elsevier Inc. All rights reserved.

AB - 5-HT1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT1A receptor-biased agonist, and F13714, a presynaptic 5-HT1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Un-like younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT1A as a treatment for cognitive deficits related to aging.(c) 2023 Elsevier Inc. All rights reserved.

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KW - Neuroplasticity

KW - Aged rats

KW - DENTATE GYRUS

KW - HIPPOCAMPAL NEUROGENESIS

KW - SYNAPTIC PLASTICITY

KW - NEUROTROPHIC FACTOR

KW - ADULT NEUROGENESIS

KW - F15599

KW - PROTEINS

KW - BRAIN

KW - COGNITION

KW - DEFICITS

U2 - 10.1016/j.neurobiolaging.2022.12.013

DO - 10.1016/j.neurobiolaging.2022.12.013

M3 - Article

C2 - 36739621

SN - 0197-4580

VL - 124

SP - 52

EP - 59

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 1

ER -

NLX-101, a 5-HT1A receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats

Abstract

Keywords

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