Revisiting Brain Tuberous Sclerosis Complex in Rat and Human: Shared Molecular and Cellular Pathology Leads to Distinct Neurophysiological and Behavioral Phenotypes

Abstract

Tuberous sclerosis complex (TSC) is a dominant autosomal genetic disorder caused by loss-of-function mutations in TSC1 and TSC2, which lead to constitutive activation of the mammalian target of rapamycin C1 (mTORC1) with its decoupling from regulatory inputs. Because mTORC1 integrates an array of molecular signals controlling protein synthesis and energy metabolism, its unrestrained activation inflates cell growth and division, resulting in the development of benign tumors in the brain and other organs. In humans, brain malformations typically manifest through a range of neuropsychiatric symptoms, among which mental retardation, intellectual disabilities with signs of autism, and refractory seizures, which are the most prominent. TSC in the rat brain presents the first-rate approximation of cellular and molecular pathology of the human brain, showing many instructive characteristics. Nevertheless, the developmental profile and distribution of lesions in the rat brain, with neurophysiological and behavioral manifestation, deviate considerably from humans, raising numerous research and translational questions. In this study, we revisit brain TSC in human and Eker rats to relate their histopathological, electrophysiological, and neurobehavioral characteristics. We discuss shared and distinct aspects of the pathology and consider factors contributing to phenotypic discrepancies. Given the shared genetic cause and molecular pathology, phenotypic deviations suggest an incomplete understanding of the disease. Narrowing the knowledge gap in the future should not only improve the characterization of the TSC rat model but also explain considerable variability in the clinical manifestation of the disease in humans.

Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism‐like neurobehavioral phenotype in a rat model

“…Results of these experiments comparing sagittal cerebellar sections of three age groups representing two genotypes are summarized in Figure 1a–f. Low magnification microscopic observation did not reveal any signs of lesion or gross structural abnormalities, or any defects in cerebellar foliation in Tsc2 +/− rats of any age, in agreement with lesions occuring exclusively in forebrain structures (Kútna et al, 2021). In all analyzed material, typical features of the cerebellar cortex were maintained, with an outer molecular layer, underlying PCs, and inner granular layers enveloping the deep white matter in all lobules (Figure 1a1–c2).…”

“…This investigation characterized the morphology and organization of the cerebellum of young, adult, and aged Tsc2+/− Eker rats, which are used as preclinical research models of familial ASD, and compared the results with age‐matched controls ( Tsc2+/+ ). We aimed to elucidate the developmental impact of mTORC1 hyperactivity on cerebellar structure, given that age presents the most important risk factor (second hit) for the development of histopathological and neurobehavioral phenotypes in this genetic model of ASD (Kútna et al, 2021). The reported equal frequency and penetrance of autosomal dominant TSC2 mutations in both sexes (Sare et al, 2020; Sauter et al, 2021; Zollner et al, 2020) warranted the inclusion of male and female rats in the current analysis.…”

“…Genetic mutations related to ASD have been extensively studied in animal models as well as in humans, providing valuable knowledge for understanding the pathobiology of both sporadic and familial forms of the disease. Fragile X syndrome (FXS) and tuberous sclerosis complex (TSC), which have mutations in FMR1 and Tsc1/2 genes, respectively (Gandhi & Lee, 2020; Kútna et al, 2021) are among the best‐characterized genetic variants of ASD, manifested with characteristic neurobehavioral symptoms.…”

“…Formed by dimerization of TSC1 and TSC2 proteins, the TSC complex controls the activity of mammalian target of rapamycin C1 (mTORC1) kinase, with its functional deficit unleashing mTORC1 from regulatory inputs, leading to unrestrained activation in cells and hypermetabolic state with related abnormal growth and proliferation (Henske et al, 2016). Using functional and biochemical tests in experimental mice, Tsc2 haploinsufficiency was shown to induce specific synaptic and network dysfunctions in the cerebrum and cerebellum (Kútna et al, 2021; Reith et al, 2011, 2013), while its deletion in PCs caused a progressive increase in neuronal size followed by apoptosis (Reith et al, 2011; 2013). Interestingly, the loss of cerebellar neurons due to Tsc2 haploinsufficiency seems to be restricted to PCs, leading to progressive motor deficit in mouse models (Reith et al, 2011).…”

All-Trans Retinoic Acid Fosters the Multifarious U87MG Cell Line as a Model of Glioblastoma

“…Variance exists when attempting to utilize cell line data and animal models due to differences between the in vivo microenvironment and the artificial conditions generated in vitro when growing cells in suspension or in adhesion to plastic surfaces. Appropriate and predictive preclinical animal glioblastoma models generated from xenografted glioma cell lines require optimized implantation sites for assisting the development of innovative GBM therapies [ 3 , 5 , 6 ].…”