De novo mutations and rare variants occurring in NMDA receptors

XiangWei, Wenshu; Jiang, Yuwu; Yuan, Hongjie

doi:10.1016/j.cophys.2017.12.013

Cited by 116 publications

(142 citation statements)

References 84 publications

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…Impaired NMDAR function observed during human NMDAR gene mutations [104], and anti-NMDAR-encephalitis [105] results in a wide range of neuropsychiatric disorders including autism spectrum disorders [106, 107], intellectual disability [108], psychosis [109], epilepsy and associated comorbidities [110, 111]. While broadly aberrant NMDAR signaling in neurons is thought to underlie a wide range of these neurological disorders, an interneuron-centric developmental NMDAR aberration is emerging central to schizophrenia-related syndromes.…”

Section: Discussionmentioning

confidence: 99%

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

Mahadevan

Mitra²,

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+ and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical and physiological properties. However, the molecular mechanisms regulating their diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype identities. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia.Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders. 14

show abstract

Section: Discussionmentioning

confidence: 99%

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

Mahadevan

Mitra²,

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The rapid expansion of whole-exome sequencing over the last decade has shown that many regions of the gene encoding GluN2A (GRIN2A) are intolerant of variation in healthy controls (Ogden et al 2017) and, instead, a large number of rare and de novo variants (>100) have been identified in patients with a range of neurodevelopmental disorders, most commonly epilepsy aphasia syndromes or other epileptic disorders, but also intellectual disability, autism, attention deficit hyperactivity disorder and schizophrenia (XiangWei et al 2018). At the most severe end of the phenotypic spectrum are epileptic encephalopathies, where epileptic activity is considered to contribute to severe cognitive and behavioural impairment (Scheffer et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy

Marwick

Hansen

Skehel

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

Key points NMDA receptors are neurotransmitter‐gated ion channels that are critically involved in brain cell communication Variations in genes encoding NMDA receptor subunits have been found in a range of neurodevelopmental disorders. We investigated a de novo genetic variant found in patients with epileptic encephalopathy that changes a residue located in the ion channel pore of the GluN2A NMDA receptor subunit. We found that this variant (GluN2A N615K ) impairs physiologically important receptor properties: it markedly reduces Mg 2+ blockade and channel conductance, even for receptors in which one GluN2A N615K is co‐assembled with one wild‐type GluN2A subunit. Our findings are consistent with the GluN2A N615K mutation being the primary cause of the severe neurodevelopmental disorder in carriers. Abstract NMDA receptors are ionotropic calcium‐permeable glutamate receptors with a voltage‐dependence mediated by blockade by Mg 2+ . Their activation is important in signal transduction, as well as synapse formation and maintenance. Two unrelated individuals with epileptic encephalopathy carry a de novo variant in the gene encoding the GluN2A NMDA receptor subunit: a N615K missense variant in the M2 pore helix ( GRIN2A C1845A ). We hypothesized that this variant underlies the neurodevelopmental disorders in carriers and explored its functional consequences by electrophysiological analysis in heterologous systems. We focused on GluN2A N615K co‐expressed with wild‐type GluN2 subunits in physiologically relevant triheteromeric NMDA receptors containing two GluN1 and two distinct GluN2 subunits, whereas previous studies have investigated the impact of the variant in diheteromeric NMDA receptors with two GluN1 and two identical GluN2 subunits. We found that GluN2A N615K ‐containing triheteromers showed markedly reduced Mg 2+ blockade, with a value intermediate between GluN2A N615K diheteromers and wild‐type NMDA receptors. Single‐channel conductance was reduced by four‐fold in GluN2A N615K diheteromers, again with an intermediate value in GluN2A N615K ‐containing triheteromers. Glutamate deactivation rates were unaffected. Furthermore, we expressed GluN2A N615K in cultured primary mouse cortical neurons, observing a decrease in Mg 2+ blockade and reduction in current density, confirming that the variant continues to have significant functional impact in neuronal systems. Our results ...

show abstract

“…Pathogenic variants in GRIN genes are associated with developmental and early onset epileptic encephalopathies (DEE) with accompanying comorbidities, such as intellectual disability, autism, aphasia, and schizophrenia (Endele et al, 2010;Hamdan et al, 2011;de Ligt et al, 2012;Lesca et al, 2013;Petrovski and Kwan, 2013;Yuan et al, 2015;Hu et al, 2016;XiangWei et al, 2018). A variety of GRIN2A variants are associated with epilepsies, presumably due to haploinsufficiency or alteration of receptor properties.…”

Section: Introductionmentioning

confidence: 99%

Modeling and treatingGRIN2Adevelopmental and epileptic encephalopathy in mice

Amador

Bostick

Olson

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

NMDA receptors (NMDAR) play crucial roles in excitatory synaptic transmission. Rare variants of GRIN2A, which encodes the GluN2A NMDAR subunit, are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). A de novo missense variant, p.Ser644Gly (c.1930A>G), was identified in a child with DEE, and Grin2a knockin mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibit altered hippocampal morphology at two weeks of age, and homozygotes exhibit lethal tonic-clonic seizures in the third week. Heterozygous adult mice display a variety of distinct features, including resistance to electrically induced partial seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with these observations, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of modeling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their extended utility in identifying and evaluating new therapies.

show abstract

De novo mutations and rare variants occurring in NMDA receptors

Cited by 116 publications

References 84 publications

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy

Modeling and treatingGRIN2Adevelopmental and epileptic encephalopathy in mice

Contact Info

Product

Resources

About