Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism

Figure 2

On the left side, the normal intestinal absorption, passage across the blood-brain barrier, and neuronal Trp uptake are shown. Neuronal Trp will be hydroxylated by tryptophan hydroxylase to 5-hydroxytryptophan (5-OH-Trp) and decarboxylated by aromatic amino acid decarboxylase to serotonin, which is then transported by the vesicular monamine transporter (VMAT-2) into presynaptic vesicles. After serotonin releases into the synaptic cleft, part of the serotonin pool will be cleared from the synaptic space by SERT into the presynaptic compartment where it will be partly recycled into vesicles or catabolized by MAO to 5HIAA. Another part of the synaptic serotonin pool will be taken up by PMAT-expressing neurons or OCT-expressing glial cells. On the right, the findings of this study suggest diverse causes contributing to lowered serotonin turnover. Abundant formation of ROS or peroxynitrite probably represents a major factor involving TPH2 enzyme dysfunction through oxidation of cysteine rich sites at the Trp binding site. In a minority of cases, a low plasma Trp as substrate for serotonin (5HT) production may be due to low dietary Trp intake or malabsorption. Rare genetic mutations of the gene encoding the serotonin reuptake transporter (SERT) lead to a gain of function of serotonin reuptake leading to diminished serotonin availability at postsynaptic receptors. Other rare mutations affect the gene encoding PMAT involving reduced clearance of serotonin from synaptic spaces, thereby disturbing serotonin turnover during early fetal brain development.