Disruption of grin2A, an Epilepsy-Associated Gene, Produces Altered Spontaneous Swim Behavior in Zebrafish

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00640235" target="_blank" >RIV/86652036:_____/25:00640235 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/67985823:_____/25:00640235 RIV/00216208:11120/25:43928646 RIV/00216208:11310/25:10499866

Výsledek na webu

<a href="https://doi.org/10.1523/JNEUROSCI.0946-25.2025" target="_blank" >https://doi.org/10.1523/JNEUROSCI.0946-25.2025</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1523/JNEUROSCI.0946-25.2025" target="_blank" >10.1523/JNEUROSCI.0946-25.2025</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Disruption of grin2A, an Epilepsy-Associated Gene, Produces Altered Spontaneous Swim Behavior in Zebrafish

Popis výsledku v původním jazyce

N-Methyl-d-aspartate receptors (NMDARs) control synaptic plasticity and brain development in a manner determined by receptor subunit composition. Pathogenic variants in GRIN2A gene, encoding the NMDAR GluN2A subunit, can cause gain or loss of function of receptors containing the affected subunit and are associated with intellectual disability and epilepsy in patients. While in vitro studies of recombinant receptors have yielded some insights, animal experimental models are essential to better understand the relationship between the molecular pathology of the variants and the disease. Here we introduce a zebrafish model of GluN2A loss of function to study system-level effects of zebrafish grin2Aa and grin2Ab gene deletion. Our electrophysiological analysis revealed functional differences between receptors containing zebrafish GluN2Aa/b and GluN2Bb paralogs comparable with mammalian receptors containing GluN2A versus GluN2B subunits. Both grin2Aa−/− and grin2Ab−/− as well as double-knock-out grin2A−/− zebrafish larvae showed increased locomotor activity in a novel environment. Proteomic analysis suggested that the relative proportion of GluN2B-containing NMDARs may be increased in grin2A mutant fish. Our results highlight fundamental similarities between zebrafish and mammalian NMDAR signaling and validate the use of zebrafish as a model organism to study the neurodevelopmental role of NMDARs. The newly created transgenic zebrafish strains complement the rodent models of GluN2A loss of function and can be used for high-throughput testing of pharmacological or genetic treatment strategies for patients with GRIN2A gene variants.

Název v anglickém jazyce

Disruption of grin2A, an Epilepsy-Associated Gene, Produces Altered Spontaneous Swim Behavior in Zebrafish

Popis výsledku anglicky

N-Methyl-d-aspartate receptors (NMDARs) control synaptic plasticity and brain development in a manner determined by receptor subunit composition. Pathogenic variants in GRIN2A gene, encoding the NMDAR GluN2A subunit, can cause gain or loss of function of receptors containing the affected subunit and are associated with intellectual disability and epilepsy in patients. While in vitro studies of recombinant receptors have yielded some insights, animal experimental models are essential to better understand the relationship between the molecular pathology of the variants and the disease. Here we introduce a zebrafish model of GluN2A loss of function to study system-level effects of zebrafish grin2Aa and grin2Ab gene deletion. Our electrophysiological analysis revealed functional differences between receptors containing zebrafish GluN2Aa/b and GluN2Bb paralogs comparable with mammalian receptors containing GluN2A versus GluN2B subunits. Both grin2Aa−/− and grin2Ab−/− as well as double-knock-out grin2A−/− zebrafish larvae showed increased locomotor activity in a novel environment. Proteomic analysis suggested that the relative proportion of GluN2B-containing NMDARs may be increased in grin2A mutant fish. Our results highlight fundamental similarities between zebrafish and mammalian NMDAR signaling and validate the use of zebrafish as a model organism to study the neurodevelopmental role of NMDARs. The newly created transgenic zebrafish strains complement the rodent models of GluN2A loss of function and can be used for high-throughput testing of pharmacological or genetic treatment strategies for patients with GRIN2A gene variants.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/GA23-04922S" target="_blank" >GA23-04922S: In vitro and in vivo studie důsledků mutací NMDA receptoru spojených s onemocněním a pokus o jejich farmakologické ovlivnění</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Neuroscience

ISSN

0270-6474

e-ISSN

1529-2401

Svazek periodika

45

Číslo periodika v rámci svazku

33

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

e0946252025

Kód UT WoS článku

001578101700005

EID výsledku v databázi Scopus

2-s2.0-105012995278