Functional aspects of early brain development are preserved in tuberous sclerosis complex (TSC) epileptogenic lesions

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F16%3A10327793" target="_blank" >RIV/00064203:_____/16:10327793 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/16:10327793

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.nbd.2016.07.014" target="_blank" >http://dx.doi.org/10.1016/j.nbd.2016.07.014</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.nbd.2016.07.014" target="_blank" >10.1016/j.nbd.2016.07.014</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Functional aspects of early brain development are preserved in tuberous sclerosis complex (TSC) epileptogenic lesions

Popis výsledku v původním jazyce

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disease characterized by several neurological disorders, the most common of which is the refractory epilepsy caused by highly epileptogenic cortical lesions. Previous studies suggest an alteration of GABAergic and glutamatergic transmission in TSC brain indicating an unbalance of excitation/inhibition that can explain, at least in part, the high incidence of epilepsy in these patients. Here we investigate whether TSC cortical tissues could retain GABA(A) and AMPA receptors at early stages of human brain development thus contributing to the generation and recurrence of seizures. Given the limited availability of pediatric human brain specimens, we used the microtransplantation method of injecting Xenopus oocytes with membranes from TSC cortical tubers and control brain tissues. Moreover, qPCR was performed to investigate the expression of GABA(A) and AMPA receptor subunits (GABA(A) alpha 1-5, beta 3, gamma 2, delta, GluA2) and cation chloride co-transporters NKCC1 and KCC2. The evaluation of nine human cortical brain samples, from 15 gestation weeks to 15 years old, showed a progressive shift towards more hyperpolarized GABAA reversal potential (E-GABA). This shift was associated with a differential expression of the chloride cotransporters NKCC1 and KCC2. Furthermore, the GluA1/GIuA2 mRNA ratio of expression paralleled the development process. On the contrary, in oocytes micro-transplanted with epileptic TSC tuber tissue from seven patients, neither the GABA(A) reversal potential nor the GluA1/GIuA2 expression showed similar developmental changes. Our data indicate for the first time, that in the same cohort of TSC patients, the pattern of both GABA(A)R and G1uA1/G1uA2 functions retains features that are typical of an immature brain. These observations support the potential contribution of altered receptor function to the epileptic disorder of TSC and may suggest novel therapeutic approaches.

Název v anglickém jazyce

Functional aspects of early brain development are preserved in tuberous sclerosis complex (TSC) epileptogenic lesions

Popis výsledku anglicky

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disease characterized by several neurological disorders, the most common of which is the refractory epilepsy caused by highly epileptogenic cortical lesions. Previous studies suggest an alteration of GABAergic and glutamatergic transmission in TSC brain indicating an unbalance of excitation/inhibition that can explain, at least in part, the high incidence of epilepsy in these patients. Here we investigate whether TSC cortical tissues could retain GABA(A) and AMPA receptors at early stages of human brain development thus contributing to the generation and recurrence of seizures. Given the limited availability of pediatric human brain specimens, we used the microtransplantation method of injecting Xenopus oocytes with membranes from TSC cortical tubers and control brain tissues. Moreover, qPCR was performed to investigate the expression of GABA(A) and AMPA receptor subunits (GABA(A) alpha 1-5, beta 3, gamma 2, delta, GluA2) and cation chloride co-transporters NKCC1 and KCC2. The evaluation of nine human cortical brain samples, from 15 gestation weeks to 15 years old, showed a progressive shift towards more hyperpolarized GABAA reversal potential (E-GABA). This shift was associated with a differential expression of the chloride cotransporters NKCC1 and KCC2. Furthermore, the GluA1/GIuA2 mRNA ratio of expression paralleled the development process. On the contrary, in oocytes micro-transplanted with epileptic TSC tuber tissue from seven patients, neither the GABA(A) reversal potential nor the GluA1/GIuA2 expression showed similar developmental changes. Our data indicate for the first time, that in the same cohort of TSC patients, the pattern of both GABA(A)R and G1uA1/G1uA2 functions retains features that are typical of an immature brain. These observations support the potential contribution of altered receptor function to the epileptic disorder of TSC and may suggest novel therapeutic approaches.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FH - Neurologie, neurochirurgie, neurovědy

OECD FORD obor

—

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Neurobiology of Disease

ISSN

0969-9961

e-ISSN

—

Svazek periodika

95

Číslo periodika v rámci svazku

November

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

9

Strana od-do

93-101

Kód UT WoS článku

000383412200009

EID výsledku v databázi Scopus

2-s2.0-84978733864