The role of hydrogen sulfide in cognitive benefits of sulfur amino acids restriction diet

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Hydrogen sulfide (H2S) is synthesized by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST) in mammalian cells, including neurons and astrocytes in the hippocampus. It facilitates synaptic plasticity (long-term potentiation, LTP) via activation of N-methyl-D-aspartate (NMDA) receptors. To date, the effect of sulfur amino acid restriction (SAAR), i.e. reducing the content of methionine and cysteine in diet, on cognitive functions and the role of H2S therein have been unclear.  Objective: To elucidate the cognitive benefits of SAAR and the underlying mechanism for H2S-mediated hippocampal plasticity. We hypothesize that SAAR triggers integrated stress response to increase endogenous H2S production, which facilitates hippocampal plasticity and memory by activating NMDA receptors. Scientific Approach: Male C57BL/6 mice will be fed with normal mouse diet as control. With different feeding schemes, body weight, % fat mass, serum triglycerides, lipid profile and blood glucose, food intake, plasma and hippocampal levels of methionine, cysteine and homocysteine will be monitored. Aim 1. To determine the effects of SAAR diet on memory, we will feed experimental mice for short-term (1-2 weeks) and long term (1-4 months) with SAAR diets (20%, 35%, and 50% reduction of methionine and cysteine content) or enhanced SAA-diet (125-200% of SAA level of the normal diet). Thereafter, we will test memory-related behaviors and hippocampal synaptic currents and plasticity. Aim 2. To explore the mechanism of SAAR-increased endogenous H2S production and the role of H2S in SAAR-enhanced memory, after SAAR diet treatment, the following measurements will be made in mouse hippocampal tissues using Western blot or qRT-PCR: a) the expression and activities of two regulators of integrated stress response, general control non-depressible 2 and activating transcription factor 4; and b) the expression of H2S-producing enzymes (CSE, CBS, MST). Whether H2S mediates the cognitive effects of SAAR will be tested by directly administering H2S salt or by selectively inhibiting endogenous H2S production. Aim 3. To investigate the mechanisms for the effects of H2S on mouse hippocampal plasticity, after SAAR or exogenous H2S application, we will examine i) the S-sulfhydration of NMDA receptors; ii) the phosphorylation of PKA and cAMP, essential for late LTP; and iii) the Ca2+ influx mediated by TRPA1 channels. Novelty and expected significance: This program will help understand the effect of SAAR on memory. By selectively focusing on SAAR, not only the key molecules responsible for the neuronal effect of total diet restriction can be identified, but also the unwanted effects of malnutrition of total diet restriction avoided. Novel nutritional approach to increase endogenous H2S levels in the brain may be devised to enhance memory or prevent the loss of memory in different biological and physiological processes.