Histidine enhances memory formation and retrieval in mice

Background and objectives: Histidine (His), one of the essential amino acids, is metabolized to neurotransmitter histamine, in the brain. Histamine controls arousal, feeding, and cognitive functions via three types of histamine receptors (H1, H2, and H3). Learning and memory consist of multiple processes including encoding, formation of short-term memory (STM) and long-term memory (LTM), retrieval, reconsolidation and extinction. However, the roles of histidine in each memory process still remains unknown. In this study, we elucidate the effects of histidine administration on memory formation and retrieval in mice. Methods: In social recognition memory task, adult mice(C57BL/6) were exposed to juvenile mice for 1.5 min every 24 hours (day1: training, day2: test). Mice were assessed social recognition memory by measuring and comparing duration of social investigation behaviors during training and test. Mice received systemic injection or oral administration of histidine with or without antagonists for histamine receptors before training or test. Results: Systemic injection of His 2 or 6 hours rather than 30 min,12, or 24 hours prior to training improved social recognition memory; mice injected His, but not vehicle, showed significant reduction of social investigate time during test compared to training. These observations suggested that His enhances memory formation. Similar memory enhancing effects of His were observed when mice received a low dose or oral administration of His. Interestingly, systemic injection of His before test improved retrieval of social recognition memory. Co-systemic injection of His with H2 or H1 antagonist blocked improvement of memory formation and retrieval by His, respectively. Conclusion: We showed that His promotes formation and retrieval of social recognition memory. Our observations suggest that His functions as a memory enhancer that improves memory performance.