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

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 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.

Reduced exploratory behavior in neuronal nucleoredoxin knockout mice

“…The phenotypes were revealed by multimodal analyses of mouse behavior in IntelliCages, Touchscreens and video-based observations in classical Maze tests, which all provide unbiased behavioral observations. IntelliCage observations have the advantage to study groups of mice in enriched home cages without observer handling, and provide complex behavioral patterns [ 45 ]. Based on the multimodal assessment we conclude that Nestin-NXN -/- mice restricted their efforts to goal-directed behavior with lower interest in adventurous, exploratory and rewarding activities including voluntary wheel running [ 46 , 47 ].…”

Low brain endocannabinoids associated with persistent non-goal directed nighttime hyperactivity after traumatic brain injury in mice

“…The time schedule for the IntelliCage experiments is shown in Fig. 4 , and the experiments followed protocols described in our previous studies 61 , 76 , 96 , 97 and were adapted to TBI mice. They are summarized in Table 1 .…”

“…In the Place Avoidance Acquisition (PAA) task (as described e.g. in 61 , 97 , mice learnt to avoid one corner, where a nosepoke triggered a red LED and an air-puff (1 s; 0.8 bar) from above the head. The door remained closed so that water access was denied.…”

Scopolamine-Induced Delirium Promotes Neuroinflammation and Neuropsychiatric Disorder in Mice

“…Lysophosphatidic acid signaling via receptors regulates diverse malignant cellular functions such as cell proliferation, motility, invasion, and metastasis 45 . Furthermore, Lpar2 antagonism prevents aging-related cognitive impairment in mice 46 . From the in ammation and immune perspective, Lpar2 functions as the negative regulator for innate immune response to prevent excess in ammation, tissue injury, and to promote homeostasis, with increased expression of Lpar2 to suppress T-helper type 2 (Th2)-driven in ammation in mice models 47 .…”