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.

最近的研究表明，突触溶血磷脂酸（LPA）通过突触前LPAR2激活增强了谷氨酸依赖性皮层兴奋性和小鼠和人类的感觉信息处理。在这里，我们使用一组行为和电生理分析研究了LPAR2缺失或拮抗作用对认知各个方面的影响。海马神经元网络活动在中年LPAR2 ^-/-小鼠中降低，而海马长期增强（LTP）增加表明LPAR2 ^-/-小鼠具有认知优势。与较低的兴奋性一致，RNAseq研究表明，幼稚的LPAR2 ^-/-中海马齿状回中神经元活动标记的转录减少^。小鼠，包括ARC，FOS，FOSB，NR4A，NPAS4和EGR2。在空间或社交学习和记忆的迷宫测试中，LPAR2 ^-/-小鼠的行为与野生型对照相似，但在需要高度关注和快速空间分辨的5选择序列反应触摸屏任务中显示出更快，更准确的响应。在IntelliCage学习实验中，LPAR2 ^-/-在白天不活跃，而在晚上通常活跃，并且在活跃期间表现出更高的准确性和对LED提示的关注。总体而言，他们通过较少的试验就保持了同等或更高的舔球成功率。LPAR2受体的药理阻滞概括了LPAR2 ^-/-表现型，其特征是使用经济角点，更强的白天休息行为和更高比例的正确试验。我们得出的结论是，LPAR2在衰老后可稳定神经网络的兴奋性，并允许更有效地利用休息时间，更好的记忆整合和在需要高度选择性注意的任务中的更好表现。治疗性LPAR2拮抗作用可缓解与衰老相关的认知功能障碍。