Astrocyte-derived lactate/NADH alters methamphetamine-induced memory consolidation and retrieval by regulating neuronal synaptic plasticity in the dorsal hippocampus

Altered neuronal lactate dehydrogenase A expression affects cognition in a sex- and age-dependent manner

“…Lactate has been shown to promote Bdnf expression through neuronal silent information regulator 1 (sirtuin 1/SIRT1) signaling, 38 , 144 N-methyl-D-aspartate (NMDA) receptor potentiation, 17 , 109 , 145 or hydroxycarboxylic acid receptor 1 (HCAR1/GPCR81) receptor activation. 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 Alternatively, lactate may trigger neural stem, precursor, or progenitor cell proliferation in the hippocampus directly through pentose phosphate pathway metabolic reprogramming 110 or zinc-dependent anaphase promotion.…”

“…For example, hippocampal KO of the pyruvate dehydrogenase E1 component alpha subunit ( Pdha1 ) causes lactate accumulation, altered monocarboxylate transporter levels, and severe impairment of spatial learning and memory in the MWM, but not recognition memory. 37 In addition, chronic systemic chemical inhibition of glycogen breakdown, and subsequent lactate production, impairs memory in young mice 17 , 21 , 22 , 28 , 29 , 52 but improves long-term potentiation in hippocampal slices 175 and short-term object recognition and location memory in old mice. 50 Interestingly, here it was observed that protein levels of ectopically expressed Ldha increased with age with a concomitant increase in intracellular lactate, as assessed by GC-MS. A recent study revealed that elevated brain lactate levels are linked to poorer working memory performance in multiple mouse models of neuropsychiatric disorders.…”

“… 12 , 13 , 14 Astrocytes support neuronal metabolism by releasing lactate that can be taken up by neurons and used for oxidative metabolism through a process known as the astrocyte-neuron lactate shuttle (ANLS). 15 , 16 While numerous studies have shown that the ANLS plays a key role in learning and memory, 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 these findings were based on experiments in which lactate transport or glycogenolysis were inhibited using a pharmaceutical approach with potentially non-cell-type specific actions or using a genetic approach targeting either astrocytes or non-specific cell types. However, the effect of directly manipulating lactate production within certain CNS cell types on cognition has not been examined before.…”

Disrupting astrocyte-neuron lactate transport prevents cocaine seeking after prolonged withdrawal

“…Previous studies have shown that astrocyte-neuron lactate transport plays an important role in drug addiction. The acquisition and persistence of cocaine-induced CPP could be blocked by pharmacological inhibition of lactate synthesis ( 26 ), and disruption of lactate transport could result in impairment of reconsolidation of reward memory and consequent failure of CPP expression in cocaine and methamphetamine ( 25 , 45 ). Furthermore, lactate may mediate the involvement of glucocorticoid receptor (GR) in altered synapse transmission in response to morphine administration ( 46 ).…”

“…Increasing evidence has demonstrated that lactate can influence both structural and functional synaptic plasticity. For instance, a higher number of intersections and total dendritic length of neurons induced by methamphetamine in the dorsal hippocampus could be reduced by DAB administration (45). Concerning functional plasticity, several studies have suggested that lactate may subserve synaptic plasticity and memory by directly enhancing the expression of plasticity-related genes in neurons, such as brain-derived neurotrophic factor (Bdnf ), activity-regulated cytoskeletal-associated protein (Arc), and c-Fos, through the downstream ERK signaling pathway (55)(56)(57).…”