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- Aug 24, 2017
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This study focuses on the dopamine breakdown product homocysteine, and elevated homocysteine could be due to overmethylation or undermethylation. This study suggests that homocysteine is a dopamine breakdown product caused by hypermethylation...the rapid breakdown of dopamine, as seen in schizophrenia.
Synaptic Effects of Dopamine Breakdown and Their Relation to Schizophrenia-Linked Working Memory Deficits
"In particular, we focus on the dopamine breakdown product homocysteine (HCY), which is consistently elevated in schizophrenia patients. Our previous studies have shown that HCY strongly reduces the desensitization of NMDA currents. Here, we show that HCY likely affects NMDA receptors in brain regions that support working memory; this is because these areas favor dopamine breakdown over transport to clear dopamine from synapses. Finally, within the context of two NMDA-based computational models of working memory, we suggest a mechanism by which HCY could give rise to the working memory deficits observed in schizophrenia patients."
"Dopamine is then methylated by COMT inside the astrocyte, generating HCY that is released back into the extracellular environment."
"We therefore suggest that a previously unappreciated consequence of COMT-mediated synaptic dopamine breakdown is the acute reduction of glycine-dependent NMDAR desensitization by HCY."
Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor
"Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine’s neurotoxic (agonist) attributes at 10–100 μM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia."
Synaptic Effects of Dopamine Breakdown and Their Relation to Schizophrenia-Linked Working Memory Deficits
"In particular, we focus on the dopamine breakdown product homocysteine (HCY), which is consistently elevated in schizophrenia patients. Our previous studies have shown that HCY strongly reduces the desensitization of NMDA currents. Here, we show that HCY likely affects NMDA receptors in brain regions that support working memory; this is because these areas favor dopamine breakdown over transport to clear dopamine from synapses. Finally, within the context of two NMDA-based computational models of working memory, we suggest a mechanism by which HCY could give rise to the working memory deficits observed in schizophrenia patients."
"Dopamine is then methylated by COMT inside the astrocyte, generating HCY that is released back into the extracellular environment."
"We therefore suggest that a previously unappreciated consequence of COMT-mediated synaptic dopamine breakdown is the acute reduction of glycine-dependent NMDAR desensitization by HCY."
Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor
"Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine’s neurotoxic (agonist) attributes at 10–100 μM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia."