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

Abstract

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.

Elevated plasma levels of glutamate in children with autism spectrum disorders

“…van Elst et al [19] found that there was a link between disturbances of the glutamate metabolism and adult autism. Similarly, our main finding was the high plasma glutamate in the ASD compared with the healthy and ID controls.…”

Increased hippocampal volumes in adults with high functioning autism spectrum disorder and an IQ>100: A manual morphometric study

“…All patients were recruited at the Freiburg Center for Diagnosis and Treatment of Autism. Study eligibility criteria are described in detail in earlier magnetic resonance spectros**copy (Tebartz van Elst et al, 2014a, 2014b and VBM studies, the latter testing the same individuals (Riedel et al, 2014).…”

“…Even large imaging studies might be insensitive towards neuropathological patterns that are only present in a specific subsample. In the present study an IQ 4100 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, 2014a). Applying the criterion of an IQ4 100 as a filter does not rule out the possibility of including syndromal forms of autism but substantially reduces the risk.…”

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

“…We further detected increased sEPSC amplitude in the Ndrg2 -/-CA1 pyramidal neurons, suggesting that elevated interstitial glutamate levels underlie the enhanced excitation. Excitatory glutamatergic system dysfunction plays an important role in the pathogenesis of neuropsychiatric disorders (58)(59)(60)(61)(62). A few studies have investigated the role of glutamate in the context of ADHD (63,64), although their conclusions are not completely consistent.…”