Glutamate and functional connectivity - support for the excitatory-inhibitory imbalance hypothesis in autism spectrum disorders

Siegel-Ramsay, Jennifer E.; Romaniuk, Liana; Whalley, Heather C.; Roberts, Neil; Branigan, Holly P.; Stanfield, Andrew C.; Lawrie, Stephen M.; Dauvermann, Maria R.

doi:10.1016/j.pscychresns.2021.111302

Cited by 22 publications

(23 citation statements)

References 89 publications

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“…Such work showed significantly higher concentrations of Glx in the amygdala-hippocampal region [ 90 ], primary sensory cortex [ 91 ], anterior cingulate cortex (ACC) [ 92 , 93 , 94 ], and auditory cortex [ 95 ], and a trend for lower Glu in the right medial temporal lobe [ 93 ], in people with ASD. Moreover, Siegel-Ramsay et al reported an association of the increased Glx concentration with reduced functional connectivity between ACC and insular, limbic, and parietal cortical regions in patients with ASD [ 96 ]. However, some works reported opposite results, specifically a reduction of Glx or Glu concentration in the right ACC [ 97 , 98 , 99 ] basal ganglia [ 100 ] and cerebellum [ 98 , 101 ] in patients with ASD compared to healthy controls.…”

Section: Glutamate Signaling In Asdmentioning

confidence: 99%

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

Montanari

Martella

Bonsi

et al. 2022

IJMS

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Disturbances in the glutamatergic system have been increasingly documented in several neuropsychiatric disorders, including autism spectrum disorder (ASD). Glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well as from studies documenting abnormalities in glutamatergic gene expression and metabolic pathways, including changes in the gut microbiota glutamate metabolism in patients with ASD. In addition, preclinical studies on animal models have demonstrated glutamatergic neurotransmission deficits and altered expression of glutamate synaptic proteins. At present, there are no approved glutamatergic drugs for ASD, but several ongoing clinical trials are currently focusing on evaluating in autistic patients glutamatergic pharmaceuticals already approved for other conditions. In this review, we provide an overview of the literature concerning the role of glutamatergic neurotransmission in the pathophysiology of ASD and as a potential target for novel treatments.

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Section: Glutamate Signaling In Asdmentioning

confidence: 99%

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

Montanari

Martella

Bonsi

et al. 2022

IJMS

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“…SHANK3 is reported to be involved in Phelan-McDermid syndrome (PMS) a form of ASD associated with moderate to severe intellectual disability (ID). Regarding SHANK2 and SHANK1, they were found altered in ASD associated with mild ID as well as in high functioning individuals (Zikopoulos and Barbas, 2013;Cochran et al, 2015;Howell and Smith, 2019;Bruining et al, 2020;Culotta and Penzes, 2020;Siegel-Ramsay et al, 2021). As to the mechanisms of GABAergic inhibitory dysfunction, the link with core ASD symptoms in humans is still under investigation.…”

Section: Models Of Excitatory/inhibitory Imbalance In Autism Spectrum Disordermentioning

confidence: 99%

“…An excitatory/inhibitory (E/I) neurotransmission imbalance in cortical neurons, using dysfunctional glutamatergic and GABAergic neurotransmission, has been reported in multiple studies, and altered glutamine levels and/or abnormal GABA/creatine levels in brain tissue or plasma are the relevant findings ( Vignoli et al, 2010 ; Carlson, 2012 ; Spooren et al, 2012 ; Gao and Penzes, 2015 ; Dickinson et al, 2016 ; Lee et al, 2017 ; Al-Otaish et al, 2018 ; Goel and Portera-Cailliau, 2019 ; Port et al, 2019 ; Bruining et al, 2020 ; Culotta and Penzes, 2020 ). Moreover, a recent study showed that high glutamate/glutamine levels have also been associated with altered functional connectivity in key brain regions for ASD, such as the dorsal anterior cingulate cortex, and insular, limbic, and parietal regions ( Siegel-Ramsay et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Heterozygous deletions eliminating exons of the neurexin-1α gene in patients with ASD have been detected, and the functional significance of this recurrent deletion is still unclear ( Frye, 2018 ). However, the role of neurexins/neuroligins in the pathogenesis of neurodevelopmental disorders has been demonstrated ( Dickinson et al, 2016 ; Al-Otaish et al, 2018 ; Wang et al, 2018 ; Goel and Portera-Cailliau, 2019 ; Port et al, 2019 ; Siegel-Ramsay et al, 2021 ). The final effect of changes in glutamatergic and GABAergic systems in ASD may be an overall increase in the ratio of excitation to inhibition (E/I) ( Howell and Smith, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Excitation/Inhibition Modulators in Autism Spectrum Disorder: Current Clinical Research

Canitano

Palumbi

2021

Front. Neurosci.

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Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication abnormalities. Heterogeneity in the expression and severity of the core and associated symptoms poses difficulties in classification and the overall clinical approach. Synaptic abnormalities have been observed in preclinical ASD models. They are thought to play a major role in clinical functional abnormalities and might be modified by targeted interventions. An imbalance in excitatory to inhibitory neurotransmission (E/I imbalance), through altered glutamatergic and GABAergic neurotransmission, respectively, is thought to be implicated in the pathogenesis of ASD. Glutamatergic and GABAergic agents have been tested in clinical trials with encouraging results as to efficacy and tolerability. Further studies are needed to confirm the role of E/I modulators in the treatment of ASD and on the safety and efficacy of the current agents.

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“…Several studies have shown altered glutamate levels in autistic individuals with a focus on regions involved in the cortico-thalamostriatal cortical (CTSC) loops (e.g. (7,(23)(24)(25)(26). For GABA, findings are a little more pronounced and point mostly to decreased levels in autism in sensorimotor, frontal and anterior cingulate and cerebellar regions (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Variation in glutamate and GABA genes and their association with brain structure and chemistry in autism

Naaijen

Arenella

Zöllner

et al. 2022

Preprint

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The excitatory/inhibitory (E/I) imbalance hypothesis posits that an imbalance between glutamatergic and GABAergic neurotransmission contributes to autism symptomatology. Whether this is due to altered GABAergic or glutamatergic functioning, or both, remains largely unknown. We integrated genetic, brain structure and brain chemistry data to investigate the relationship between E/I genetic variation and expression, glutamate concentrations and cortical thickness (CT). Participants (60 autism and 104 neurotypical controls, aged 8-13 years) underwent magnetic resonance imaging and spectroscopy for glutamate quantification in the anterior cingulate cortex (ACC) and left dorsal striatum. Genetic involvement in these regional glutamate concentration levels was investigated using competitive gene-set association and polygenic scores (PGS). Further, glutamate as well as GABA gene-set expression profiles were investigated in relation to CT. Aggregated genetic variation in the glutamate gene-set was associated with ACC but not striatal glutamate concentrations. PGS analysis, however, showed a genome-wide PGS for autism to be predictive of striatal but not ACC glutamate levels. Expression profiles of GABAergic-but not glutamatergic genes were associated with differences in cortical thickness between groups. This study showed differential involvement of aggregated glutamatergic and GABAergic genetic variation in brain structure and chemistry in autism, which suggests regional variability in E/I imbalance.

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Glutamate and functional connectivity - support for the excitatory-inhibitory imbalance hypothesis in autism spectrum disorders

Cited by 22 publications

References 89 publications

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

Excitation/Inhibition Modulators in Autism Spectrum Disorder: Current Clinical Research

Variation in glutamate and GABA genes and their association with brain structure and chemistry in autism

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