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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 (<jats:italic>Tsc2+\/\u2212<\/jats:italic>) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18\u2009m.o. Eker rats, to determine possible structural correlates of an autism\u2010like 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\u2010related demyelination of central tract of the vermis, as evident from reduced level of myelin\u2010basic protein in the <jats:italic>arbora vitae<\/jats:italic>. We also observed a higher number of astrocytes in <jats:italic>Tsc2+\/\u2212<\/jats:italic> rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild\u2010type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in <jats:italic>Tsc2+\/\u2212<\/jats:italic> rats of older age. The convergent evidence for a variety of age\u2010dependent 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\u2010like behavioral phenotype in this model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Lay Summary<\/jats:title><jats:p>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\u2010dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro\u2010behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age\u2010related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/aur.2688","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T08:18:59Z","timestamp":1645172339000},"page":"791-805","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cerebellar demyelination and neurodegeneration associated with <scp>mTORC1<\/scp> hyperactivity may contribute to the developmental onset of <scp>autism\u2010like<\/scp> neurobehavioral phenotype in a rat model"],"prefix":"10.1002","volume":"15","author":[{"given":"Viera","family":"K\u00fatna","sequence":"first","affiliation":[{"name":"Department of Experimental Neurobiology National Institute of Mental Health  Klecany Czech 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