Functional changes of AMPA responses in human induced pluripotent stem cell–derived neural progenitors in fragile X syndrome

Achuta, Venkat Swaroop; Möykkynen, Tommi; Peteri, Ulla-Kaisa; Turconi, Giorgio; Rivera, Claudio; Keinänen, Kari; Castrén, Maija

doi:10.1126/scisignal.aan8784

Cited by 49 publications

(58 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lending credence to this, previous studies have reported that differentially expressed genes in the blood of subjects with ASD are enriched for regulatory targets of CHD8 18 and FMR1 22 , two well-known rASD genes. Similarly, both lymphoblastoid cells of subjects with ASD and hiPSC-derived models of fragile-X syndrome show over-expression of mir-181 with a potential role in the disorder 23 . Likewise, leukocytes from toddlers with ASD show perturbations in biological processes such as cell proliferation, differentiation, and microtubules [24][25][26][27] , and these coincide with dysregulated processes seen in hiPSC-derived neural progenitors and neurons from individuals with ASD and brain enlargement 28,29 .…”

Section: Introductionmentioning

confidence: 98%

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

Gazestani

Pramparo

Nalabolu

et al. 2018

Preprint

View full text Add to dashboard Cite

Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. Highconfidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers.These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms. that the network is mostly preserved at the co-expression level between ASD leukocytes and prenatal brain.Specifically, the direction of correlations (i.e., positive or negative) in the leukocyte transcriptome of subjects with ASD is mostly preserved in prenatal and early postnatal brain ( Fig. 2d). Importantly, this preservation of co-expression was significantly higher in the DE-ASD network than in the DE-TD network (p-value <10 -16 ; Fig. S6). rASD genes are associated with the DE-ASD networkWe next analyzed the DE-ASD network in the context of other studies to test the relevance of our DE-ASD network to ASD. Parikshak et al. previously reported gene co-expression modules associated with cortical laminae development during prenatal and early postnatal ages 11 . A subset of these modules show enrichment in rASD genes 11 . We examined the overlap of our leukocyte-derived network with all modules from Parikshak et al 11 . The DE-ASD network preferentially overlapped with rASD gene-enriched modules from that study ( Fig. 2e). This suggests that our DE-ASD network is functionally related to rASD genes during neocortical development. Our DE-ASD network also overlapped with the networks of rASD genes reported in other studies 7,9 , indicating the robustness of the results (Fig. 2e). Intriguingly, the prenatal brain co-expression network of high-confidence rASD genes was more similar to that of ASD leukocytes than TD leukocytes ( Fig. 2f), suggesting that neurodevelopmental transcriptional programs related to rASD genes might be more active in the leukocyte transcriptome of toddlers with ASD than in that of TD toddlers.With the observed overlap patterns, we next tested for enrichment of rASD genes in the DE-ASD network. For this analysis, we considered different rASD gene lists of different size and varying confidence levels (Methods). Surprisingly, this analysis demonstrated that rASD genes are not enriched in the DE-ASD network (p-value >0.19). The DE-ASD network is enriched for regulatory targets of rASD genesMany high confidence rASD...

show abstract

Section: Introductionmentioning

confidence: 98%

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

Gazestani

Pramparo

Nalabolu

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, we have previously observed decreased GluA2 expression following neonatal hypoxic seizures in wild type (WT) rats, which contributes to social interaction deficits, elevated activity-dependent Ca 2ϩ influx, altered downstream signaling, and increased epileptogenesis (Sanchez et al, 2001;Rakhade et al, 2008;Lippman-Bell et al, 2013Rosenberg et al, 2018). Finally, altered GluA2 subunit expression has been observed in several neurodevelopmental disorders, such as Rett syndrome, Fragile X syndrome, tuberous sclerosis, and RAB39B-associated mental retardation (Talos et al, 2008;Mignogna et al, 2015;Li et al, 2016;Achuta et al, 2018), pointing to a critical role of GluA2 in disease pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

2019

View full text Add to dashboard Cite

Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5 R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.

show abstract

“…Furthermore, the search for FMRP-interacting proteins has resulted into the identification of dozens of partners, including ion channels (Bardoni et al, 2006 ; Ferron, 2016 ; and this study). Consistently with these findings, ion homeostasis defects in FXS neurons have been described (Chen et al, 2003 ; Meredith et al, 2007 ; Brown et al, 2010 ; Deng et al, 2013 ; Ferron et al, 2014 ; Hebert et al, 2014 ; Zhang et al, 2014 ; Contractor et al, 2015 ; Myrick et al, 2015 ; Wahlstrom-Helgren and Klyachko, 2015 ; Achuta et al, 2018 ). In particular, FMRP has been reported to directly interact with two members of the Voltage Gated Calcium Channels (VGCC) family, namely Ca v 2.1 and Ca v 2.2 (Ferron et al, 2014 ).…”

Section: Introductionmentioning

confidence: 57%

New Insights Into the Role of Cav2 Protein Family in Calcium Flux Deregulation in Fmr1-KO Neurons

Castagnola

Delhaye

Folci

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and a leading cause of autism, results from the loss of expression of the Fmr1 gene which encodes the RNA-binding protein Fragile X Mental Retardation Protein (FMRP). Among the thousands mRNA targets of FMRP, numerous encode regulators of ion homeostasis. It has also been described that FMRP directly interacts with Ca2+ channels modulating their activity. Collectively these findings suggest that FMRP plays critical roles in Ca2+ homeostasis during nervous system development. We carried out a functional analysis of Ca2+ regulation using a calcium imaging approach in Fmr1-KO cultured neurons and we show that these cells display impaired steady state Ca2+ concentration and an altered entry of Ca2+ after KCl-triggered depolarization. Consistent with these data, we show that the protein product of the Cacna1a gene, the pore-forming subunit of the Cav2.1 channel, is less expressed at the plasma membrane of Fmr1-KO neurons compared to wild-type (WT). Thus, our findings point out the critical role that Cav2.1 plays in the altered Ca2+ flux in Fmr1-KO neurons, impacting Ca2+ homeostasis of these cells. Remarkably, we highlight a new phenotype of cultured Fmr1-KO neurons that can be considered a novel cellular biomarker and is amenable to small molecule screening and identification of new drugs to treat FXS.

show abstract

Functional changes of AMPA responses in human induced pluripotent stem cell–derived neural progenitors in fragile X syndrome

Cited by 49 publications

References 83 publications

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

New Insights Into the Role of Cav2 Protein Family in Calcium Flux Deregulation in Fmr1-KO Neurons

Contact Info

Product

Resources

About