Cargando…

Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2

Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cogniti...

Descripción completa

Detalles Bibliográficos
Autores principales: Fischer, Caroline, Endle, Heiko, Schumann, Lana, Wilken-Schmitz, Annett, Kaiser, Julia, Gerber, Susanne, Vogelaar, Christina F., Schmidt, Mirko H. H., Nitsch, Robert, Snodgrass, Isabel, Thomas, Dominique, Vogt, Johannes, Tegeder, Irmgard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897625/
https://www.ncbi.nlm.nih.gov/pubmed/32468095
http://dx.doi.org/10.1007/s00018-020-03553-4
_version_ 1783653707270848512
author Fischer, Caroline
Endle, Heiko
Schumann, Lana
Wilken-Schmitz, Annett
Kaiser, Julia
Gerber, Susanne
Vogelaar, Christina F.
Schmidt, Mirko H. H.
Nitsch, Robert
Snodgrass, Isabel
Thomas, Dominique
Vogt, Johannes
Tegeder, Irmgard
author_facet Fischer, Caroline
Endle, Heiko
Schumann, Lana
Wilken-Schmitz, Annett
Kaiser, Julia
Gerber, Susanne
Vogelaar, Christina F.
Schmidt, Mirko H. H.
Nitsch, Robert
Snodgrass, Isabel
Thomas, Dominique
Vogt, Johannes
Tegeder, Irmgard
author_sort Fischer, Caroline
collection PubMed
description Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2(−/−) mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2(−/−) mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2(−/−) mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2(−/−) mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2(−/−) were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2(−/−) phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better  performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03553-4) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-7897625
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-78976252021-03-05 Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2 Fischer, Caroline Endle, Heiko Schumann, Lana Wilken-Schmitz, Annett Kaiser, Julia Gerber, Susanne Vogelaar, Christina F. Schmidt, Mirko H. H. Nitsch, Robert Snodgrass, Isabel Thomas, Dominique Vogt, Johannes Tegeder, Irmgard Cell Mol Life Sci Original Article Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2(−/−) mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2(−/−) mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2(−/−) mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2(−/−) mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2(−/−) were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2(−/−) phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better  performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03553-4) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-05-28 2021 /pmc/articles/PMC7897625/ /pubmed/32468095 http://dx.doi.org/10.1007/s00018-020-03553-4 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article
Fischer, Caroline
Endle, Heiko
Schumann, Lana
Wilken-Schmitz, Annett
Kaiser, Julia
Gerber, Susanne
Vogelaar, Christina F.
Schmidt, Mirko H. H.
Nitsch, Robert
Snodgrass, Isabel
Thomas, Dominique
Vogt, Johannes
Tegeder, Irmgard
Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
title Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
title_full Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
title_fullStr Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
title_full_unstemmed Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
title_short Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
title_sort prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of lpar2
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897625/
https://www.ncbi.nlm.nih.gov/pubmed/32468095
http://dx.doi.org/10.1007/s00018-020-03553-4
work_keys_str_mv AT fischercaroline preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT endleheiko preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT schumannlana preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT wilkenschmitzannett preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT kaiserjulia preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT gerbersusanne preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT vogelaarchristinaf preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT schmidtmirkohh preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT nitschrobert preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT snodgrassisabel preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT thomasdominique preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT vogtjohannes preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2
AT tegederirmgard preventionofageassociatedneuronalhyperexcitabilitywithimprovedlearningandattentionuponknockoutorantagonismoflpar2