Kutna, Viera, O'Leary, Valerie Brid, Hoschl, Cyril and Ovsepian, Saak V. (2022) Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model. Autism Research, 15 (5). pp. 791-805. ISSN 1939-3792 (Print), 1939-3806 (Online) (doi:10.1002/aur.2688)

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	autism spectrum disorder; cerebellum; mTORC1 signaling; demyelination; Purkinje neurons; microglia activation; synaptophysin
Subjects:	Q Science > QH Natural history > QH301 Biology
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	13 May 2022 10:45
URI:	http://gala.gre.ac.uk/id/eprint/35232

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