Glutamate receptor mutations in psychiatric and neurodevelopmental disorders

Soto, David; Altafaj, Xavier; Sindreu, Carlos; Bayés, Àlex

doi:10.4161/cib.27887

Cited by 68 publications

(59 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Researchers have identified de novo point mutations and protein truncations in GluN2B in multiple studies (O'Roak et al 2012, Tarabeux et al 2011); many of these mutations and truncations are predicted to be disruptive. A CNV containing GluN2A has also been identified (Soto et al 2014). Expression of the GluN2 subunit of NMDARs is developmentally regulated such NE38CH07-Huganir ARI 28 March 2015 11:53 that GluN2B expression predominates very early in development, whereas GluN2A expression increases later (Sheng et al 1994).…”

Section: Autism Spectrum Disordersmentioning

confidence: 97%

“…Researchers have identified SCZ-associated genetic variations in the NMDAR subunits GRIN1, GRIN2A, and GRIN2B, as well as in multiple components of NMDAR signaling and scaffolding complexes (Soto et al 2014). Mice expressing ∼5% of normal GluN1 levels display behavioral abnormalities related to SCZ (Mohn et al 1999).…”

Section: Schizophreniamentioning

confidence: 98%

“…Reflecting the critical role for iGluRs in mediating information flow throughout the brain, investigators have identified mutations in all classes of iGluRs in patients with ID (see Soto et al 2014 for a review). The first glutamate receptor gene mutation reported in ID was GRIA3 (GluA3), which was mapped onto an X-chromosome break point-induced translocation (Gécz et al 1999).…”

Section: Intellectual Disabilitymentioning

confidence: 99%

See 2 more Smart Citations

Glutamate Synapses in Human Cognitive Disorders

Volk

Chiu

Sharma

et al. 2015

Annu. Rev. Neurosci.

224

179

View full text Add to dashboard Cite

Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

show abstract

Section: Autism Spectrum Disordersmentioning

confidence: 97%

Section: Schizophreniamentioning

confidence: 98%

Section: Intellectual Disabilitymentioning

confidence: 99%

See 1 more Smart Citation

Glutamate Synapses in Human Cognitive Disorders

Volk

Chiu

Sharma

et al. 2015

Annu. Rev. Neurosci.

224

179

View full text Add to dashboard Cite

show abstract

“…The profound increase in the current produced by this mutation seems likely to drive aberrant excitation and potentially contribute to neuronal loss and consequently the patients' clinical symptoms. In subsequent years, a large number of missense mutations and deletions/truncations (.100) have been identified through whole exome and genome sequencing (reviewed by Soto et al, 2014;Burnashev and Szepetowski, 2015) and are scattered across all domains in NMDA receptor subunits (Supplemental Table S2; Tables 2 and 3) Myers et al, 2011;Tarabeux et al, 2011;de Ligt et al, 2012;O'Roak et al, 2012;Carvill et al, 2013b, DeVries andPatel, 2013;Epi4K and Epilepsy Phenome/ Genome Project, 2013;Freunscht et al, 2013;Lemke et al, 2013Lemke et al, , 2014Lesca et al, 2013;Adams et al, 2014;Andreoli et al, 2014;Fromer et al, 2014;Kenny et al, 2014;Pierson et al, 2014;Redin et al, 2014;Venkateswaran et al, 2014;Yuan et al, 2014;Burnashev and Szepetowski, 2015;Ohba et al, 2015;Turner et al, 2015). More recently, several case-control studies have isolated de novo and inherited mutations in the GRIN2A gene in patients diagnosed with different forms of epilepsy, including continuous spike-and-waves during slow-wave sleep syndrome, epileptic encephalopathy, Landau-Kleffner syndrome, and Rolandic epilepsy (Endele et al, 2010;Carvill et al, 2013b;Lemke et al, 2013;Lesca et al, 2013; reviewed by Burnashev and Szepetowski, 2015).…”

Section: Gaba/glutamate Receptor Mutations In Neurologic Diseasesmentioning

confidence: 99%

“…Even more recently, a surprising number of disease-associated glutamate receptor mutations have been identified, with .80% found within the NMDA receptor subfamily (Table 2; reviewed by Soto et al, 2014;Burnashev and Szepetowski, 2015). In both GABA and glutamate receptor families, mutations that disrupt protein structure, conformation, abundance, or localization have been described.…”

Section: Introductionmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

186

176

View full text Add to dashboard Cite

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

show abstract

AMPA Receptors

Striessnig¹,

Watson²,

Greger³

2020

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Neuronal communication relies on rapid signalling through chemical synapses. The majority of excitatory neurotransmission in the central nervous system is mediated by binding of glutamate to a family of postsynaptic glutamate receptors. Among these, α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid receptors (AMPARs) mediate fast excitatory synaptic transmission and play a critical role in the synaptic plasticity that underlies learning and memory. AMPAR function is influenced on multiple levels by a combination of transcriptional modifications, post‐translational regulation, and association with a multitude of auxiliary subunits. These processes give rise to a diverse array of receptors with unique properties for their specific role in brain function. Due to their central role in neuronal signalling, malfunction in AMPAR production or regulation can cause severe neurological and neuropsychiatric diseases. Since their cloning in the 1990s, much has been learned about AMPAR structure, assembly and trafficking, demonstrating the molecular complexity that underlies brain function. Key Concepts AMPA receptors mediate fast glutamatergic synaptic transmission. The receptor has a highly flexible, four‐layered, domain organisation. AMPARs associate with a diverse array of auxiliary subunits. Post‐transcriptional modifications and distinct combinations of core and auxiliary subunits generate structurally and functionally diverse AMPA receptors. The composition of AMPA receptor complexes varies between cell‐types and at different synapses. Regulation of synaptic AMPA receptors expression is highly dynamic. Synaptic AMPA receptor anchoring and accumulation is essential for neurotransmission. Modulation of AMPA receptor function and/or trafficking allows synaptic plasticity. AMPA receptor dysfunction is involved in various neurological diseases.

show abstract

Glutamate receptor mutations in psychiatric and neurodevelopmental disorders

Cited by 68 publications

References 48 publications

Glutamate Synapses in Human Cognitive Disorders

Glutamate Synapses in Human Cognitive Disorders

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

AMPA Receptors

Contact Info

Product

Resources

About