Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies

Eltokhi, Ahmed; Santuy, Andrea; Merchán-Pérez, Ángel; Sprengel, Rolf

doi:10.3390/ijms22010059

Cited by 32 publications

(25 citation statements)

References 252 publications

(303 reference statements)

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“…Autism spectrum disorder is associated with the dysregulation of glutamate, dopamine, and serotonin in the brains of patients [ 99 , 100 , 101 ]. Increases of Bacteroides , Prevotella , Lachnospiracea_incertae_sedis , and Megamonas as well as decreases of Clostridium XlVa , Eisenbergiella , Clostridium IV , Flavonifractor , Escherichia / Shigella , Haemophilus , Akkermansia , and Dialister have been detected in patients with autism [ 102 ].…”

Section: Influence Of Gut Microbe-regulated Neurotransmitter Synthesis On Cognitionmentioning

confidence: 99%

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

2021

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Emerging evidence indicates that gut microbiota is important in the regulation of brain activity and cognitive functions. Microbes mediate communication among the metabolic, peripheral immune, and central nervous systems via the microbiota–gut–brain axis. However, it is not well understood how the gut microbiome and neurons in the brain mutually interact or how these interactions affect normal brain functioning and cognition. We summarize the mechanisms whereby the gut microbiota regulate the production, transportation, and functioning of neurotransmitters. We also discuss how microbiome dysbiosis affects cognitive function, especially in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

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Section: Influence Of Gut Microbe-regulated Neurotransmitter Synthesis On Cognitionmentioning

confidence: 99%

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

2021

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“…[ 36 , 37 ]). On the one hand, some studies support the hyperglutamate theory in ASD and are based on increased glutamate concentrations in the serum and plasma, on the upregulation of NMDA receptors in animal models induced with valproic acid, or on the behavioural ameliorations triggered by antagonists of glutamatergic receptors [ 38 ]. On the other hand, some other studies support the hypoglutamate theory in ASD and rely on dysfunction of certain glutamatergic receptors and on beneficial effects of glutamatergic agonists in ASD [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

“…On the one hand, some studies support the hyperglutamate theory in ASD and are based on increased glutamate concentrations in the serum and plasma, on the upregulation of NMDA receptors in animal models induced with valproic acid, or on the behavioural ameliorations triggered by antagonists of glutamatergic receptors [ 38 ]. On the other hand, some other studies support the hypoglutamate theory in ASD and rely on dysfunction of certain glutamatergic receptors and on beneficial effects of glutamatergic agonists in ASD [ 38 ]. Studies using the in vivo and non-invasive method of magnetic resonance spectroscopy (MRS) in autistic adults showed that the level of Glx (glutamate and glutamine) depended on the brain region: Glx was either increased (amygdala–hippocampal complex [ 39 ], auditory cortex [ 40 ], sensorimotor cortex [ 41 ], anterior cingulate cortex (ACC) [ 42 ], cerebellum [ 43 ]), decreased (ACC [ 44 , 45 ], central nuclei [ 46 , 47 ]) or not different from NT (frontal regions [ 46 , 48 – 51 ], parietal regions [ 39 , 44 , 46 ], occipital regions [ 49 , 52 ], cingulate cortex [ 50 , 53 ], thalamus [ 44 ]).…”

Section: Introductionmentioning

confidence: 99%

Prediction learning in adults with autism and its molecular correlates

et al. 2021

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Background According to Bayesian hypotheses, individuals with Autism Spectrum Disorder (ASD) have difficulties making accurate predictions about their environment. In particular, the mechanisms by which they assign precision to predictions or sensory inputs would be suboptimal in ASD. These mechanisms are thought to be mostly mediated by glutamate and GABA. Here, we aimed to shed light on prediction learning in ASD and on its neurobiological correlates. Methods Twenty-six neurotypical and 26 autistic adults participated in an associative learning task where they had to learn a probabilistic association between a tone and the rotation direction of two dots, in a volatile context. They also took part in magnetic resonance spectroscopy (MRS) measurements to quantify Glx (glutamate and glutamine), GABA + and glutathione in a low-level perceptual region (occipital cortex) and in a higher-level region involved in prediction learning (inferior frontal gyrus). Results Neurotypical and autistic adults had their percepts biased by their expectations, and this bias was smaller for individuals with a more atypical sensory sensitivity. Both groups were able to learn the association and to update their beliefs after a change in contingency. Interestingly, the percentage of correct predictions was correlated with the Glx/GABA + ratio in the occipital cortex (positive correlation) and in the right inferior frontal gyrus (negative correlation). In this region, MRS results also showed an increased concentration of Glx in the ASD group compared to the neurotypical group. Limitations We used a quite restrictive approach to select the MR spectra showing a good fit, which led to the exclusion of some MRS datasets and therefore to the reduction of the sample size for certain metabolites/regions. Conclusions Autistic adults appeared to have intact abilities to make predictions in this task, in contrast with the Bayesian hypotheses of ASD. Yet, higher ratios of Glx/GABA + in a frontal region were associated with decreased predictive abilities, and ASD individuals tended to have more Glx in this region. This neurobiological difference might contribute to suboptimal predictive mechanisms in ASD in certain contexts.

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“…Glutamate is one of the main neurotransmitters, and iGluRs (ligand-gated ionotropic glutamate receptors) play a crucial role in synaptic plasticity and memory. In the cerebral cortex, glutamatergic neurons comprise up to 80% of the brain’s total metabolic activity under non-stimulated conditions [ 200 , 201 ]. Disruption of iGluRs has been associated with neuropathological conditions, such as Alzheimer’s disease and brain damage.…”

Section: Theories and Mechanism Of Pathophysiologymentioning

confidence: 99%

Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer’s Disease

et al. 2021

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Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are neurodevelopmental and neurodegenerative disorders affecting two opposite ends of life span, i.e., childhood and old age. Both disorders pose a cumulative threat to human health, with the rate of incidences increasing considerably worldwide. In the context of recent developments, we aimed to review correlated symptoms and genetics, and overlapping aspects in the mechanisms of the pathogenesis of ASD and AD. Dementia, insomnia, and weak neuromuscular interaction, as well as communicative and cognitive impairments, are shared symptoms. A number of genes and proteins linked with both disorders have been tabulated, including MECP2, ADNP, SCN2A, NLGN, SHANK, PTEN, RELN, and FMR1. Theories about the role of neuron development, processing, connectivity, and levels of neurotransmitters in both disorders have been discussed. Based on the recent literature, the roles of FMRP (Fragile X mental retardation protein), hnRNPC (heterogeneous ribonucleoprotein-C), IRP (Iron regulatory proteins), miRNAs (MicroRNAs), and α-, β0, and γ-secretases in the posttranscriptional regulation of cellular synthesis and processing of APP (amyloid-β precursor protein) have been elaborated to describe the parallel and overlapping routes and mechanisms of ASD and AD pathogenesis. However, the interactive role of genetic and environmental factors, oxidative and metal ion stress, mutations in the associated genes, and alterations in the related cellular pathways in the development of ASD and AD needs further investigation.

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Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies

Cited by 32 publications

References 252 publications

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

Prediction learning in adults with autism and its molecular correlates

Symptomatic, Genetic, and Mechanistic Overlaps between Autism and Alzheimer’s Disease

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