Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: Evidence in support of the excitatory/inhibitory imbalance hypothesis

Molecular Psychiatry (Impact Factor: 14.5). 07/2014; 19(12):1314-1325. DOI: 10.1038/mp.2014.62
Source: PubMed


Over the last few years, awareness of autism spectrum disorder (ASD) in adults has increased. The precise etiology of ASD is still unresolved. Animal research, genetic and postmortem studies suggest that the glutamate (Glu) system has an important role, possibly related to a cybernetic imbalance between neuronal excitation and inhibition. To clarify the possible disruption of Glu metabolism in adults with high-functioning autism, we performed a magnetic resonance spectroscopy (MRS) study investigating the anterior cingulate cortex (ACC) and the cerebellum in adults with high-functioning ASD. Twenty-nine adult patients with high-functioning ASD and 29 carefully matched healthy volunteers underwent MRS scanning of the pregenual ACC and the left cerebellar hemisphere. Metabolic data were compared between groups and were correlated with psychometric measures of autistic features. We found a significant decrease in the cingulate N-acetyl-aspartate (NAA) and the combined Glu and glutamine (Glx) signals in adults with ASD, whereas we did not find other metabolic abnormalities in the ACC or the cerebellum. The Glx signal correlated significantly with psychometric measures of autism, particularly with communication deficits. Our data support the hypothesis that there is a link between disturbances of the cingulate NAA and Glx metabolism, and autism. The findings are discussed in the context of the hypothesis of excitatory/inhibitory imbalance in autism. Further research should clarify the specificity and dynamics of these findings regarding other neuropsychiatric disorders and other brain areas.Molecular Psychiatry advance online publication, 22 July 2014; doi:10.1038/mp.2014.62.

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Available from: Ludger Tebartz van Elst, Aug 11, 2014
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    • "For example, the importance of the glutamatergic system in the hippocampus in depression vulnerability has been extensively described (Sanacora et al., 2012). However, an altered glutamate signaling or an imbalance of excitatory and inhibitory neurotransmitters has been proposed as central mechanism for a number of psychiatric disorders, including also schizophrenia (Moghaddam and Javitt, 2012), autism (Tebartz van Elst et al., 2014) or bipolar disorders (Chen et al., 2010). Interestingly , proline, one of the main amino acids transported by SLC6A15, is involved in glutamate synthesis (P erez-Arellano et al., 2010). "
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    ABSTRACT: Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Psychiatric Research 09/2015; 68:261-269. DOI:10.1016/j.jpsychires.2015.07.012 · 3.96 Impact Factor
    • "Even large imaging studies might be insensitive towards neuropathological patterns that are only present in a specific subsample. In the present study an IQ > 100 was an eligibility criterion in an attempt to recruit non-syndromal ASD without severe monogenetic and oligogenetic syndromes and more related etiologies (Tebartz van Elst et al., 2014). Applying the criterion of an IQ>100 as a filter does not rule out the possibility of including syndromal forms of autism but substantially reduces the risk. "
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    ABSTRACT: Previous studies concerning the volumes of the amygdala and the hippocampus in autism spectrum disorders (ASD) show inconsistent results. We acquired magnetic resonance images of 30 individuals with ASD and individually matched controls. All participants had an IQ>100 to increase the likelihood of including non-syndromal forms of ASD. Manually defined amygdala volumes showed no significant group difference, while hippocampi were significantly enlarged in ASD. This finding is discussed with regard to the 'intense world hypothesis'. Copyright © 2015. Published by Elsevier Ireland Ltd.
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    ABSTRACT: One popular major theory of neurotransmitter dysfunction is an imbalance in excitation and inhibition (EI theory).The EI imbalance theory is thought to impact widely across neural circuits mediating language, social, and cognitive functions, and could potentially explain some aspects of the autism phenotype. Evidence from genetic and molecular studies provide support for abnormal suppression of γ-aminobutyric acid (GABA) function and an overabundance of glutamatergic transmission as potential mechanisms of this hyperexcitability. Proton magnetic resonance spectroscopy (1H-MRS) is a potentially exciting neuroimaging tool allowing in vivo estimation of glutamate and GABA neurotransmitters in people with autism spectrum disorder (ASD). We reviewed all available published studies of ASD reporting 1H-MRS measurement of glutamate, GABA, or both neurotransmitters. Glutamate results across studies are equivocal, with nearly equal numbers of studies reporting increases or decreases in autism. However, the age of the individuals studied appears to relate to the direction of the findings, suggesting that future longitudinal studies of glutamate should be conducted. Although fewer GABA-specific studies have been published, all have reported decreases in autism. Overall, from 1H-MRS studies alone, support for the glutamate side of the EI imbalance theory is tenuous, but this is an indication of serious limitations in the 1H-MRS literature. For GABA dysfunction, the GABA findings to date are consistent for reduced concentration in autism; however, there are only a few published 1H-MRS studies of GABA in autism, all from studies with a small number of subjects. More studies, particularly longitudinal developmental studies across both child and adult development, are needed.
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