Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11120%2F22%3A43923009" target="_blank" >RIV/00216208:11120/22:43923009 - isvavai.cz</a>
Alternative codes found
RIV/00023752:_____/22:43920790
Result on the web
<a href="https://doi.org/10.1002/aur.2688" target="_blank" >https://doi.org/10.1002/aur.2688</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/aur.2688" target="_blank" >10.1002/aur.2688</a>
Alternative languages
Result language
angličtina
Original language name
Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model
Original language description
The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/-) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18 m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/- rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/- rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. LAY SUMMARY: This study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30103 - Neurosciences (including psychophysiology)
Result continuities
Project
<a href="/en/project/LO1611" target="_blank" >LO1611: Sustainability for The National Institute of Mental Health</a><br>
Continuities
S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Autism Research
ISSN
1939-3792
e-ISSN
1939-3806
Volume of the periodical
15
Issue of the periodical within the volume
5
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
791-805
UT code for WoS article
000757233300001
EID of the result in the Scopus database
2-s2.0-85124765916