mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00542433" target="_blank" >RIV/67985823:_____/21:00542433 - isvavai.cz</a>

Alternative codes found

RIV/00023752:_____/21:43920559 RIV/00216208:11110/21:10426469 RIV/00216208:11130/21:10426469 RIV/00216208:11310/21:10426469

Result on the web

<a href="https://doi.org/10.1186/s11689-021-09357-2" target="_blank" >https://doi.org/10.1186/s11689-021-09357-2</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s11689-021-09357-2" target="_blank" >10.1186/s11689-021-09357-2</a>

Result language

angličtina

Original language name

mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus

Original language description

Background Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. Methods At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). Results Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). Conclusions These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/LO1611" target="_blank" >LO1611: Sustainability for The National Institute of Mental Health</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

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

Name of the periodical

Journal of Neurodevelopmental Disorders

ISSN

1866-1947

e-ISSN

1866-1955

Volume of the periodical

13

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

17

Pages from-to

14

UT code for WoS article

000641466700001

EID of the result in the Scopus database

2-s2.0-85104459923