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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    • "CC in children with ASD [ Bejjani et al . , 2012 ] ; yet another found increased gluta - mate ( Glu ) in ACC in children with ASD [ Joshi et al . , 2013 ] . Three additional studies examined adults with ASD , finding increased NAA / Cho in the ACC [ Oner et al . , 2007 ] , reduced NAA , and combined Glutamate / Glutamine ( Glx ) in pregenual ACC [ van Elst et al . , 2014 ] , and reduced Glx in right ACC [ Bernardi et al . , 2011 ] compared to TD peers . PCC is another region of multiple abnormalities in ASD . For instance , reduced connectivity between the PCC and medial prefrontal cortex has been reported in a mixed group of children and adolescents with ASD [ Rudie et al . , 2012 ] . Lynch et al . [ 2"
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    ABSTRACT: Neuroimaging studies have uncovered structural and functional alterations in the cingulate cortex in individuals with autism spectrum disorders (ASD). Such abnormalities may underlie neurochemical imbalance. In order to characterize the neurochemical profile, the current study examined the concentration of brain metabolites in dorsal ACC (dACC) and posterior cingulate cortex (PCC) in high-functioning adults with ASD. Twenty high-functioning adults with ASD and 20 age-and-IQ-matched typically developing (TD) peers participated in this Proton magnetic resonance spectroscopy (1H-MRS) study. LCModel was used in analyzing the spectra to measure the levels of N-Acetyl aspartate (NAA), choline (Cho), creatine (Cr), and glutamate/glutamine (Glx) in dACC and PCC. Groups were compared using means for the ratio of each metabolite to their respective Cr levels as well as on absolute internal-water-referenced measures of each metabolite. There was a significant increase in Cho in PCC for ASD adults, with a marginal increase in dACC. A reduction in NAA/Cr in dACC was found in ASD participants, compared to their TD peers. No significant differences in Glx/Cr or Cho/Cr were found in dACC. There were no statistically significant group differences in the absolute concentration of NAA, Cr, Glx, or NAA/Cr, Cho/Cr, and Glx/Cr in the PCC. Differences in the metabolic properties of dACC compared to PCC were also found. Results of this study provide evidence for possible cellular and metabolic differences in the dACC and PCC in adults with ASD. This may suggest neuronal dysfunction in these regions and may contribute to the neuropathology of ASD. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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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.
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    • "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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