5-Aminolevulinic acid improves spatial recognition memory in mice

The production of 5-aminolevulinic acid (5-ALA) is the rate-limiting step in heme biosynthesis, and is thus essential for maintaining cellular respiration and the activities of various heme-containing enzymes. Recently, it was reported that exogenous 5-ALA can alleviate cognitive impairments in animal models. To elucidate the contributions of 5-ALA to cognition and investigate the underlying molecular mechanisms, we examined the impact of 5-ALA administration on both novel objective recognition (NOR) and spatial recognition memories in male ddY mice and on long-term potentiation (LTP) in hippocampal slices isolated from these mice. Both intracerebroventricular and oral administration of 5-ALA enhanced object recognition memory as evidenced by increased time spent investigating a novel object compared to a familiar object in the NOR test. Further, oral administration of 5-ALA improved the spontaneous alternation performance in the Y-maze test. Administration of 5-ALA also increased the glutamate/GABA ratio in dorsal hippocampus, ventral hippocampus, and entorhinal cortex, brain regions essential for recognition memory. Further, direct 5-ALA administration increased the LTP of excitatory postsynaptic potentials in hippocampal slices induced by theta-burst stimulation (TBS), and this LTP enhancement was completely mitigated by pretreatment with 1-naphthyl acetyl spermine, an antagonist of Ca2⁺-permeable AMPA receptors lacking the GluR2 subunit (CP-AMPARs). We suggest that 5-ALA improves spatial recognition memory by enhancing the TBS-induced expression or activity of postsynaptic CP-AMPARs, resulting in greater and longer-lasting LTP. Endogenous 5-ALA appears critical for maintaining cognitive function in the mammalian central nervous system, while exogenous supplementation could be a useful strategy for the treatment of cognitive dysfunction.