In a search for a specific and sensitive biomarker of autism, a great quantity of research has focused on the study of neurotransmitters, measuring their blood concentrations, marking receptor density and quantifying the production and degradation of specific neurochemicals. The proton magnetic resonance spectroscopy imaging (1H-MRS), a technique permitting non-invasive quantification of endogenous neurochemicals, has provided useful information, none of which unfortunately provided a firm and conclusive theory.
However, one of the most important neurochemical theories of autism supported by diverse different research approaches is the excitation/inhibition imbalance theory. Based on extensive evidence of glutamate-and GABA-related abnormalities found in the autistic brain, it has been hypothesized that a complex lack of local inhibition and long-distance excitation during development and later in life could be a common factor to the diverse developmental findings in autism.
One of the first findings that pointed to an excitation/inhibition dysregulation in autism was the fact that around 30% of patients with ASD develop epileptic seizures during their lifetime and approximately 60% have epileptiform EEG activity during sleep [62
]. Also, as noted above, an underdevelopment of inhibitory neurons, allowing the processing of individual stimuli, has been found in several brain areas [9
There is evidence of glutamate dysregulation in the ASD population, although none point to a single gene or protein in the glutamate signaling system, but indicate a complex pathophysiology in the functioning of this neurotransmitter in general. Aldred et al.
(2003) measured glutamate blood levels in ASD patients and their families and found higher than normal concentrations [64
]. In the same study the peripheral levels of phenylalanine, lysine and asparagine were also elevated, while glutamine concentration was reduced. Moreno-Fuyenmayor et al.
(1996) also found lower blood levels of glutamine [65
] but Shinohe et al.
] failed to observe reduced glutamine concentration. Both studies found higher glutamate blood levels, and the latter reported a significant correlation between the glutamate upregulation and the severity of clinical presentation. In conclusion, the peripheral levels of glutamate are definitely altered in relation to autism, but measuring neurochemical blood levels is perhaps too dependent on pre-medication, nutrition and comorbidity as to be a reliable marker of autism.
Secondly, the research of glutamate system related genes has shown some substantial aberrations. An upregulation of AMPA receptor subunits GluR1, GluR2 and GluR3 were found through cDNA and mRND quantification in post-mortem cerebellar and hippocampal tissue, but interestingly, a lower overall AMPA receptor density was reported in the same cerebellar samples [67
]. An excess of transmission of maternal haplotype for another glutamate receptor, GluR6 was found by Jamain et al.
(2002) and confirmed later in a large scale study on 174 parents-child trios [68
An additional parent-of-origin specific region, the 15q12 was found to have significant association with autism susceptibility [69
]. This region contains a cluster of GABA(A) receptor subunit genes (GABRB3, GABRA5, and GABRG3), again pointing to the excitation/inhibition dysregulation theory. Duplications in this region have been reported and confirmed in numerous studies of autism [69
]. A quantification of GABRA1–3 and GABRB3 receptors in the cerebellum and frontal and parietal cortex by Fatemi et al.
(2009) showed decreased receptor density. The parietal GABA receptor density was reduced for all quantified receptors, while other results varied with receptor type and localization [72
]. Also, a reduced GABRB density was found in ACC and FG [73
], areas known for morphological alterations in autism [23
Glutamate decarboxylase (GAD), an enzyme that metabolizes glutamate into GABA, was also found to be significantly reduced in the parietal cortex and cerebellum of ASD patients [74
], thus showing that both neurotransmitter systems are inseparable in the etiology of autism.
A recent 1
H-MRS study by Bernardi et al.
(2011) has measured concentrations of neurotransmitters in varying brain regions in high-functioning, non-medicated adults with autism and controls. Unfortunately, 1
H-MRS cannot yet distinct between glutamate, glutamine, and GABA signals, so these compounds are measured together and termed Glx. However, a significant depletion of Glx concentration was found in ACC in this study, providing important evidence for the glutamate-GABA dysregulation theory. Although only high-functioning patients were used in the study, no IQ correlation was noted, implicating that this finding can be generalized to the whole ASD population [75
Further neurochemical imbalances were found in other 1 H-MRS studies, such as widespread and localized reductions of N-acetyl-aspartate, choline-containing compounds and myo-inositol concentrations, but more studies of this type will be needed to support these findings. The precise 1H-MRS technology will surely prove to be very useful in the future.
A large quantity of genetic research has also implicated that the genes involved in some ASD cases are also connected to the excitation/inhibition imbalance. There is a subgroup of genes conclusively linked to autism, which, through regulation of synaptic plasticity and receptor expression, mediate the metabolism of glutamate and GABA, thus resulting in ASD-like symptoms. The genes most implicated are SHANK3
, neuroligin 3 (NL3
) and 4 (NL4
] (See ).
Serotonin (5HT) dysregulation has been mentioned as a possible etiology of autism, based on consistent findings of higher than normal blood levels of 5HT [89
]. Hyperserotonemia has been reported in about a third of all the autistic patients, but a correlation between severity of clinical presentation and levels of 5HT has not been established. The elevated blood levels of autistic patients seem to be age-independent, while normally developing children show a progressive decrease in 5HT blood levels [89
]. The increased concentration of 5HT is also found in parents and siblings of ASD patients with hyperserotonemia [89
]. Some findings report a negative influence of high 5HT levels on language learning [91
] and self-injuring behavior [92
] as well as IQ levels [89
]. Symptoms of autism comorbidities such as depression, irritability and obsessive-compulsive disorder have been shown to improve with selective 5HT reuptake inhibitors (SSRI) therapy [68
]. 5HT plays an important role in early brain development when serving as a growth factor and regulating proliferation and maturation, both key events known to be disrupted in autism, which makes it a possible primary defect in ASD etiology [68
Research on dopamine in autism was motivated based on clinical evidence showing reduced aggressive, hyperactive and self-destructing behavior in patients under treatment with dopamine D2
receptor antagonists. This amelioration of symptoms has been attributed to D2
-mediated glutamate release, again pointing to the excitation/inhibition imbalance theory [75
]. The peripheral quantification of homovanilic acid (HVA), a metabolite of dopamine, has proven to be insignificantly altered in autism. Furthermore, central HVA measurements were inconstant, showing evidence of elevated, normal or lowered concentrations. Studies of endogenous opioids and norepinephrine in autism have also failed to show conclusive results [68
Finally, two neuropeptides, vasopressin (AVP) and especially oxytocin (OT) have been suspected to be involved in the pathophysiology of ASD. OT and AVP are similar nonapeptides produced in the hypothalamus and secreted from the pituitary. Oxytocin plays crucial roles during child birth, breastfeeding and sexual arousal [93
]. Perhaps even more importantly, research performed on knock-out OT mice has confirmed it to be vital in mother-child bonding, pair-bonding, as well as in social recognition and attachment behavior (trustfulness) in general, thus giving OT dysregulation a possible role in the etiology of autism [96
]. The hypothesis that autistic children are affected by a prolonged exposure to OT during birth leading to a downregulation of OT receptors has been refuted [99
]. However, decreased plasma concentration of OT in ASD patients has been reported, providing an interesting explanation of the male: female ratio in patients with autism. A higher female sensitivity to OT could prevent the development of autistic traits in females, while the same decrease of OT concentration could lead to symptoms of ASD in males [68