Figure 1. Distribution of Biogenic Amine Neurotransmitters in the Human Brain.
Current knowledge dictates that neurotransmitter system dysfunction could be the cause of autism spectrum disorder (ASD), by affecting neuronal migration, differentiation, synaptogenesis, and eventually developmental process of the brain. Major projection pathways of the biogenic amine neurotransmitter systems in the human brain. Shown are the projections of the serotonin, dopamine, norepinephrine, and epinephrine systems using the neurotransmitters. The views are midsagittal sections through the human brain, depicting the medial surface of the right hemisphere; the front pole is at left. In each image, the primary source of the biogenic amine is bold type and colored accordingly.
Figure 2. Biosynthetic Pathway and Distribution of Serotonin Neurotransmitter in the Human Brain.
(a) Serotonin is derived from the amino acid tryptophan by a two-step process that requires the enzymes tryptophan-5-hydroxylase and a decarboxylase (right panel). (b) Major projection pathway of the monoamine neurotransmitter system in the human brain. Shown are the projections of the serotonin system using the neurotransmitter (left panel). The views are midsagittal sections through the human brain, depicting the medial surface of the right hemisphere; the front pole is at left. In each image, the primary source of the biogenic amine is bold type and colored accordingly.
- Hyper- or hypo-production of serotonin (5-HT) itself.
- A problem with the serotonin transporter substance, 5-HTT/SERT.
- Abnormalities in the provision and action of serotoninergic receptor cells.
Figure 3. Glutamate Synthesis and Cycling.
Glutamate synthesis and cycling between neurons and glia, the so-called ‘glutamate – glutamine cycle.’ Glutamate is the major excitatory neurotransmitter in the brain. Glutamate is a nonessential amino acid that does not cross the blood-brain barrier (BBB) and must be synthesized from local precursors. Glutamine is the most prevalent precursor in synaptic terminals for glutamate synthesis. Glutamine is released by glial cells and, once within the presynaptic terminal of the neuron, it is metabolized to glutamate by the mitochondrial enzyme glutaminase. Glutamate can also be synthesized by the process of transamination of 2-oxoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle. Thus, some of the glucose metabolized by neurons can also be utilized for glutamate synthesis. [VGLUT – vesicular glutamate transporter; EAAT – excitatory amino acid transporter; SN1 – system N1 transporter (glutamine transporter); SAT2 – system A transporter]
Figure 4. GABA Synthesis, Release, and Uptake.
GABA is the major inhibitory neurotransmitter in the brain. Glucose is the predominant precursor for GABA synthesis. Initially, glucose is metabolized to glutamate by the tricarboxylic acid (TCA) cycle enzymes, although glutamine and pyruvate can also act as precursor substances. GABAergic neurons express glutamic acid decarboxylase (GAD), which is found almost uniquely in these neurons. GAD catalyzes the conversion of glutamate to GABA. GAD requires pyridoxal phosphate as a cofactor for optimal activity. Since pyridoxal phosphate is derived from vitamin B6, a B6 deficiency can lead to reduced GABA synthesis. ‘The significance of this become obvious after a disastrous series of infant deaths, linked to the omission of vitamin B6 from infant formula.’ The absence of B6 resulted in a substantial reduction in GABA content of the brain, and the ensuing loss of synaptic inhibition caused seizures in newborns that in some cases were fatal. More recently, seizures due to B6 deficiency have been reported in adults. [GABA – gamma amino butyric acid; GABA receptors – gamma amino butyric receptors; GAT – GABA transporter type 1, 2, or 3]
Figure 5. Biosynthetic Pathway and Distribution of Dopamine Neurotransmitter in the Human Brain.
(a) Dopamine is synthesized from the amino acids, phenylalanine or tyrosine via sequential reactions catalyzed primarily by phenylalanine hydroxylase, tyrosine hydroxylase, and DOPA decarboxylase (right panel). (b) Major projection pathway of the biogenic amine neurotransmitter system in the human brain. Shown are the projections of the dopamine system using the neurotransmitter (left panel). The views are midsagittal sections through the human brain, depicting the medial surface of the right hemisphere; the front pole is at left. In each image, the primary source of the biogenic amine is bold type and colored accordingly.
- Emotion dysregulation
- Anomalies of attention
- Executive dysfunction
- Repetitive behavior
- Motor abnormalities
Figure 6. Neuropeptide Amino Acid Sequences – Pituitary Peptides.
Oxytocin is a naturally occurring nine-peptide amino acid that is synthesized in the hypothalamus and stored and released by the posterior pituitary. Oxytocin is important in a broad range of behaviors, including bonding, nurturing, and social recognition. Vasopressin is structurally similar to oxytocin. Vasopressin is a nine-amino acid peptide hormone synthesized by hippocampal magnocellular and parvocellular neurons. It is synthesized as pre-pro-vasopressin in the neuron cell bodies and is cleaved into vasopressin prior to reaching the posterior pituitary, where it is then released. Vasopressin is involved in multiple systemic functions, including maintenance of cardiovascular homeostasis, increased water retention, and regulation of the body’s response to stress. [ACTH – adreno corticotropic hormone; α-MSH – alpha-melanocyte-stimulating hormone]
- Oxytocin, a naturally occurring peptide, is key for social perception, learning, and mediating pair bonding in animals and humans.
- Three key genetic pathways modulate oxytocin expression, receptors, and release. These have been linked to individual differences in social cognition, behavior, and risk for ASD.
- Nasal administration of oxytocin has been associated with increased social engagement and aptitude along with alterations in functional brain activity.
- There is evidence for oxytocin action across social communication and restricted and repetitive behavior domains, in reductions in anxiety, and in alterations in sensory sensitivity.
- Oxytocin interventions studies have had inconclusive findings, although particular promise has been found for pediatric ASD.
- Vasopressin has been implicated in ASD through studies investigating its concentrations, genetic linkage, and receptor expression. However, evidence across these studies is varied and often contradictory.
- Preclinical evidence suggests that vasopressin influences social communication behavior to a certain extent.
- Preliminary clinical data investigating V1AR (vasopressin receptor 1A or arginine vasopressin receptor 1A, AVPR1A) antagonism and vasopressin administration also indicated that vasopressin has a role in social communication in individuals with and without ASD.
Figure 7. Biosynthetic Pathway and Distribution of Norepinephrine and Epinephrine Neurotransmitters in the Human Brain.
(a) The amino acid tyrosine is the precursor for all three catecholamines, viz., dopamine, norepinephrine, and epinephrine. Dopamine is derived from the amino acid tyrosine. Norepinephrine is produced from dopamine and is a precursor molecule for the hormone epinephrine (right panel). (b) Major projection pathways of the catecholamine neurotransmitter systems in the human brain. Shown are the projections of the norepinephrine and epinephrine systems using the neurotransmitters (left panel). The views are midsagittal sections through the human brain, depicting the medial surface of the right hemisphere; the front pole is at left. In each image, the primary source of the biogenic amine is bold type and colored accordingly.
- possibly resulting from evolutionary pressures, or
- to the influence of sex hormones on brain development postnatally rather than prenatally, and/or
- a masculinized brain might be attributable to postnatal environmental factors.
Table 1. Partial list of neurotransmitters organized by chemical properties.
|Neurotransmitters Organized by Chemical Properties|
|Monoamines & Acetylcholine||L-Amino Acids||Peptides|
|Dopamine||Glutamate||Enkephalins (endogenous opioid peptides)|
|Norepinephrine||GABA||β-Endorphin (endogenous opioid peptide)|
|Epinephrine||Aspartate||Dynorphins (endogenous opioid peptide)|
|Histamine||Neuropeptide Y (NPY)|
|Acetylcholine||Peptide YY (PYY)|
|Adenosine triphosphate (ATP)||Corticotrophin releasing hormone (CRH)|
|Vasoactive intestinal polypeptide (VIP)|
|Nitric oxide (NO)||Anadamide (endocannabinoid)||Bombesin|
|Carbon monoxide (CO)||2-Arachidonoylglycerol (endocannabinoid)||Gelanin|
|Vasoactive intestinal polypeptide (VIP)|
|[Adapted and modified from Hyman SE, Curr Biol. 2005 Mar 8;15(5):R154-8.]|
Summary and Conclusions
Finally, since a secure understanding of the neurochemistry of autism or of subsets within the spectrum would provide a sound basis for the development and testing of drug and dietary treatments for autism, in this context, further research in this emerging field of neurochemistry of autism is of potential practical importance and would warrant further investigation.
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