Developmental effects of constitutive mTORC1 hyperactivity and environmental enrichment on structural synaptic plasticity and behaviour in a rat model of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition causing a range of social and communication impairments. Although the role of multiple genes and environmental factors has been reported, the effects of the interplay between genes and environment on the onset and progression of the disease remains elusive. We housed wild‐type (Tsc2+/+) and tuberous sclerosis 2 deficient (Tsc2+/−) Eker rats (ASD model) in individually ventilated cages or enriched conditions and conducted a series of behavioural tests followed by the histochemical analysis of dendritic spines and plasticity in three age groups (days 45, 90 and 365). The elevated plus‐maze test revealed a reduction of anxiety by enrichment, whereas the mobility of young and adult Eker rats in the open field was lower compared to the wild type. In the social interaction test, an enriched environment reduced social contact in the youngest group and increased anogenital exploration in 90‐ and 365‐day‐old rats. Self‐grooming was increased by environmental enrichment in young and adult rats and decreased in aged Eker rats. Dendritic spine counts revealed an increased spine density in the cingulate gyrus in adult Ekers irrespective of housing conditions, whereas spine density in hippocampal pyramidal neurons was comparable across all genotypes and groups. Morphometric analysis of dendritic spines revealed age‐related changes in spine morphology and density, which were responsive to animal genotype and environment. Taken together, our findings suggest that under TSC2 haploinsufficiency and mTORC1 hyperactivity, the expression of behavioural signs and neuroplasticity in Eker rats can be differentially influenced by the developmental stage and environment.

Biomolecules to Biomarkers? U87MG Marker Evaluation on the Path towards Glioblastoma Multiforme Pathogenesis

“…This research focused on the examination of histological sections obtained from patients displaying the classical pattern of GBM and elicited various responses to chemotherapy. Where possible, analysis was performed in parallel with sections from an Eker rat glioma model (inclusion criteria: 18-month-old males, subcortical tumors in the cerebrum, tsc2 +/− genotype [ 32 , 33 ]). All experimental procedures were approved by the local Committee for Animal Protection and were conducted in accordance with the Animal Protection Code of the Czech Republic and the directive of the European Community Council on the use of laboratory animals (2010/63/EC).…”

“…Images were acquired with a Leica TCS SP8X confocal system (Leica Microsystems, Mannheim, Germany) using an HCX PL APO 40_/1.30 Oil objective or for low magnification HCX PLS-APO 5× and appropriate excitation with 405 and 488 nm lasers, which were then analyzed with LAS AF software (Version 2.6 Light, Leica Microsystems, Mannheim, Germany) and ImageJ 1.47 software (NIH, Bethesda, MD, USA). The brightness and contrast of images were adjusted in a standardized manner for all images as previously described [ 32 , 33 ]. All images and graphs were generated and assembled in figures using SPSS (version 6) and Microsoft PowerPoint (Microsoft Office 10).…”

Analysis of the action mechanisms and targets of herbal anticonvulsants highlights opportunities for therapeutic engagement with refractory epilepsy

“…1). Pathological changes causing hyperactivity of mTOR signaling are known to lead to neuronal dysplasia with neurodevelopmental disorders, including autism and epilepsy [44,[89][90][91]. Other etiologies of epilepsy, such as brain injury and neonatal hypoxia-ischemia, have also been linked to hyperactivity of the mTOR pathway [92].…”