Hydrogen sulfide (H₂S), a gas known for its toxicity, is produced endogenously from l-cysteine in mammalian tissues, particularly in the brain. This study investigates the role of H₂S as an endogenous neuromodulator. Key findings include: 1. **Enzyme Expression and Function**: Cystathionine β-synthase (CBS), an H₂S-producing enzyme, is highly expressed in the hippocampus and cerebellum. CBS inhibitors hydroxylamine and amino-oxycetate suppress H₂S production, while a CBS activator, S-adenosyl-l-methionine (AdoMet), enhances H₂S production. 2. **Physiological Concentrations and Effects**: Physiological concentrations of H₂S (130 μM) selectively enhance NMDA receptor-mediated responses and facilitate the induction of hippocampal long-term potentiation (LTP). High concentrations of H₂S (≥320 μM) inhibit synaptic transmission in the hippocampus. 3. **Mechanisms of Action**: H₂S facilitates LTP only when applied associatively with a weak tetanic stimulation, suggesting its involvement in associative learning. Unlike nitric oxide (NO) and carbon monoxide (CO), which act as retrograde messengers, H₂S's effect on LTP does not require NMDA receptor activation. 4. **Disulfide Bonds and Thiol Redox Sites**: H₂S selectively enhances NMDA receptor-mediated responses, indicating that disulfide bonds or free thiols in NMDA receptors are not primarily involved in its potentiating effect. 5. **Conclusion**: Endogenous H₂S, primarily produced by CBS, may play a role in associative learning and synaptic plasticity in the brain. Further research is needed to develop more specific and potent inhibitors of H₂S-producing enzymes to confirm these findings.Hydrogen sulfide (H₂S), a gas known for its toxicity, is produced endogenously from l-cysteine in mammalian tissues, particularly in the brain. This study investigates the role of H₂S as an endogenous neuromodulator. Key findings include: 1. **Enzyme Expression and Function**: Cystathionine β-synthase (CBS), an H₂S-producing enzyme, is highly expressed in the hippocampus and cerebellum. CBS inhibitors hydroxylamine and amino-oxycetate suppress H₂S production, while a CBS activator, S-adenosyl-l-methionine (AdoMet), enhances H₂S production. 2. **Physiological Concentrations and Effects**: Physiological concentrations of H₂S (130 μM) selectively enhance NMDA receptor-mediated responses and facilitate the induction of hippocampal long-term potentiation (LTP). High concentrations of H₂S (≥320 μM) inhibit synaptic transmission in the hippocampus. 3. **Mechanisms of Action**: H₂S facilitates LTP only when applied associatively with a weak tetanic stimulation, suggesting its involvement in associative learning. Unlike nitric oxide (NO) and carbon monoxide (CO), which act as retrograde messengers, H₂S's effect on LTP does not require NMDA receptor activation. 4. **Disulfide Bonds and Thiol Redox Sites**: H₂S selectively enhances NMDA receptor-mediated responses, indicating that disulfide bonds or free thiols in NMDA receptors are not primarily involved in its potentiating effect. 5. **Conclusion**: Endogenous H₂S, primarily produced by CBS, may play a role in associative learning and synaptic plasticity in the brain. Further research is needed to develop more specific and potent inhibitors of H₂S-producing enzymes to confirm these findings.