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

Autor: Caroline Fischer, Dominique Thomas, Irmgard Tegeder, Robert Nitsch, Heiko Endle, Susanne Gerber, Isabel Faria Snodgrass, Christina F. Vogelaar, Julia Kaiser, Lana Schumann, Annett Wilken-Schmitz, Johannes Vogt, Mirko H H Schmidt
Rok vydání: 2020
Předmět:
Male
Aging
EGF Family of Proteins
Touchscreen
Long-Term Potentiation
Hippocampus
Biology
Hippocampal formation
IntelliCage
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
Cognition
0302 clinical medicine
Memory
Tandem Mass Spectrometry
Animals
Premovement neuronal activity
Hippocampal excitability
Receptors
Lysophosphatidic Acid
Maze Learning
Molecular Biology
Chromatography
High Pressure Liquid
030304 developmental biology
Mice
Knockout
Neurons
Pharmacology
Principal Component Analysis
0303 health sciences
Arc (protein)
Lysophosphatidic acids
Dentate gyrus
Calcium-Binding Proteins
Brain
Discriminant Analysis
Long-term potentiation
Cell Biology
Mice
Inbred C57BL
Liver
Dentate Gyrus
Molecular Medicine
Original Article
Female
Memory consolidation
Neuroscience
030217 neurology & neurosurgery
FOSB
Zdroj: Cellular and Molecular Life Sciences
ISSN: 1420-9071
1420-682X
DOI: 10.1007/s00018-020-03553-4
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: