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P2‐148: AEROBIC GLYCOLYSIS IS REQUIRED FOR SPATIAL MEMORY CONSOLIDATION BUT NOT MEMORY RETRIEVAL IN MICE
Author(s) -
Harris Richard A.,
Lone Asad,
Lim Heeseung,
Scholl Timothy J.,
Cumming Robert C.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.834
Subject(s) - glycolysis , pyruvate dehydrogenase complex , pyruvate kinase , lactate dehydrogenase , oxidative phosphorylation , anaerobic glycolysis , chemistry , morris water navigation task , in vivo , memory consolidation , endocrinology , medicine , biochemistry , biology , enzyme , hippocampus , microbiology and biotechnology
Background:Aerobic glycolysis (AG) is defined as the non-oxidative metabolism of glucose to generate lactate, even when oxygen is not rate limiting. Recent studies have shown that AG occurs in approximately 1015% of the human brain, predominately in various regions of the frontal cortex. Moreover, AG, and associated lactate production, is believed to be critical for long-term memory formation. We previously demonstrated that lactate dehydrogenase A (Ldha) and pyruvate kinase 1 (Pdk1), key enzymes which promote AG, exhibit an age-dependent decline in the frontal cortex of wild type mice. Moreover, improved memory performance in aged wild-type mice correlates with elevated expression of both Pdk1 and Ldha. Methods:We tested the effect of dichloroacetate (DCA), an inhibitor of Pdk1, on spatial memory in mice using the Morris Water Maze. In vivo hyperpolarized C-pyruvate magnetic resonance spectroscopy was employed to measure the rate of conversion of pyruvate to lactate in the brain. Changes in enzyme expression and the phosphorylation state of pyruvate dehydrogenase (PDH) was assessed by immunoblot analysis of tissue extracts and immunofluorescent staining of brain sections. Results: DCA administration led to the decreased conversion of pyruvate to lactate in the mouse brain, concomitant with a reduction in phosphorylation of the PDH complex. Intraperitoneal (IP) injection of DCA during training caused a significant delay in learning which subsequently resulted in impaired spatial memory assessed by both short-term and long-term probe trials. Surprisingly, IP injection of DCA only before the probe trials had no effect on memory performance. Conclusions:Our findings indicate that AG plays a key role during memory acquisition and consolidation but is less important for retrieval of established memories. Thus, regional activation of AG may be critical for learning-dependent synaptic plasticity rather than the activation of signalling cascades required for retrieval or reconsolidation of established spatial memories. Understanding the metabolic requirements for learning and memory retrieval will help elucidate mechanisms underlying memory decline during aging and in Alzheimer’s disease.