TY  - JOUR
A1  - Fischer, Caroline
A1  - Endle, Heiko
A1  - Schumann, Lana
A1  - Wilken-Schmitz, Annett
A1  - Kaiser, Julia
A1  - Gerber, Susanne
A1  - Vogelaar, Christina F.
A1  - Schmidt, Mirko Hans Heinrich
A1  - Nitsch, Robert
A1  - Snodgrass, Isabel
A1  - Thomas, Dominique Jeanette
A1  - Vogt, Johannes
A1  - Tegeder, Irmgard
T1  - Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2
T2  - Cellular and molecular life sciences
N2  - 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.
KW  - Lysophosphatidic acids
KW  - Cognition
KW  - Touchscreen
KW  - IntelliCage
KW  - Long-term potentiation
KW  - Hippocampal excitability
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63669
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-636699
SN  - 1420-9071
N1  - The study was supported by the Deutsche Forschungsgemeinschaft (CRC1039, A03 to IT,  CRC1080, A03 to IT, CRC1080, B05 to JV, SFB1193 A05 to SG). Open Access funding provided by Projekt DEAL.
VL  - 78.2020
IS  - 3
SP  - 1029
EP  - 1050
PB  - Springer International Publishing AG
CY  - Cham (ZG)
ER  -