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 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.

Automated summary

Recent studies show that synaptic lysophosphatidic acids (LPAs) can enhance cortical excitability and sensory information processing through presynaptic LPAR2 activation in mice and humans. Deletion or antagonism of LPAR2 in mice resulted in decreased hippocampal neuronal network activity, increased hippocampal long-term potentiation (LTP), and improved cognitive performance in tasks requiring high attention and fast spatial discrimination. LPAR2(-/-) mice exhibited similar performance to wild-type controls in maze tests, but showed faster and more accurate responses in tasks requiring selective attention.