Differential effects of L- and D-lactate on memory encoding and consolidation: Potential role of HCAR1 signaling

Abstract The process of memory consolidation is energy-demanding and brain energy deficits result in memory impairments. Indeed, L-lactate, a preferred neuronal energy substrate, enhances the formation of memory, while blockade of the neuronal uptake of L-lactate by either pharmacological means or using its enantiomer D-lactate, impairs memory. Beyond metabolism, both enantiomers of lactate also have signaling properties through the hydroxycarboxylic acid receptor 1 (HCAR1). Thus far, paradigms testing for an effect of lactate on memory modulation have ignored HCAR1 signaling while also mainly performing manipulations before learning and using intracranial administration techniques. Using an inhibitory avoidance (IA) memory protocol, the present study examined the effects of systemic administration of both L- and D-lactate as well as the specific HCAR1 agonist 3,5-dihydroxybenzoic acid (3,5-DHBA) across pre- and post-training periods. We found that post-training subcutaneous injections of either 3,5-DHBA or D-lactate significantly enhanced memory compared to saline controls, whereas L-lactate had no effect, suggesting that HCAR1 signaling in the absence of lactate metabolism supports memory consolidation processes. When administered 15 minutes prior to training, D-lactate and 3,5-DHBA impaired memory compared to saline controls. In contrast, L-lactate treated rats showed memory enhancements as compared to D-lactate-treated rats. Taken together, these results suggest different roles for lactate at different memory stages. It is likely that a metabolic role is at play during learning while HCAR1 signaling may play a greater role during consolidation.