Fischer, Caroline, Endle, Heiko, Schumann, Lana, Wilken-Schmitz, Annett, Kaiser, Julia, Gerber, Susanne, Vogelaar, Christina F., Schmidt, Mirko H. H. ORCID: 0000-0001-7411-8835, Nitsch, Robert, Snodgrass, Isabel, Thomas, Dominique, Vogt, Johannes and Tegeder, Irmgard . Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2. Cell. Mol. Life Sci.. BASEL: SPRINGER BASEL AG. ISSN 1420-9071

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Abstract

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 naive 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fischer, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Endle, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumann, LanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilken-Schmitz, AnnettUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiser, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerber, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogelaar, Christina F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Mirko H. H.UNSPECIFIEDorcid.org/0000-0001-7411-8835UNSPECIFIED
Nitsch, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Snodgrass, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tegeder, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-332672
DOI: 10.1007/s00018-020-03553-4
Journal or Publication Title: Cell. Mol. Life Sci.
Publisher: SPRINGER BASEL AG
Place of Publication: BASEL
ISSN: 1420-9071
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MEDIAL PREFRONTAL CORTEX; PROGRANULIN DEFICIENT MICE; CA3 PYRAMIDAL NEURONS; SYNAPTIC PLASTICITY; MOUSE MODEL; HIPPOCAMPAL HYPERACTIVITY; AMPA RECEPTORS; DISCRIMINATION; MEMORY; SLEEPMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33267

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