Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin

Abstract

Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the mTORC1 signaling pathway in TSC has been consistently demonstrated. Here we address abnormal brain development in TSC by inactivating the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell lineages. Tsc1Emx1-Cre conditional knockout (CKO) animals die by 25 days of life. Their brains have increased size and contain prominent large cells within the cerebral cortex that have greatly increased mTORC1 signaling and decreased mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic astrocytes and decreased myelination were also found. Tsc1Emx1-Cre CKO mice were then treated with rapamycin to see if the premature death and brain abnormalities can be rescued. Postnatal rapamycin treatment completely prevented premature death and largely reversed the glia pathology but not abnormal neuronal lamination. These findings support a model that loss of function of the TSC genes in embryonic neural progenitor cells causes cortical malformations in patients with TSC. The dramatic effect of rapamycin suggests that even with extensive multi-lineage abnormalities, a postnatal therapeutic window may exist for patients with TSC.

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

“…We previously found that suppression of Rheb-GTPase activity with farnesyl transferase inhibitors almost completely rescued spine synapse formation 14 . Thus, a non-canonical pathway such as this Rheb-syntenin signalling may participate in some of the symptomatic manifestations in TSC [40][41][42] . Indeed, knockdown and knockout of brain syntenin restored contextual fear discrimination deficits in Tsc2 þ / À rats and mice, respectively (unpublished data).…”

Tuberous sclerosis and epilepsy: Role of astrocytes

“…Emx1 Cre conditional knockout mice contain enlarged dysmorphic astrocytes within the cerebral cortex (Carson et al, 2012).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Transgenic overexpression of mTOR in murine brains culminates in cortical atrophy and neurodegeneration (Kassai, Sugaya, Noda, Nakao, & Maeda, 2014), while conditional knockout of Tsc1 (TSC complex subunit 1), an mTOR inhibitor, has also successfully induced the neurodegenerative abnormalities in mouse brains, a phenocopy of AD pathophysiology (Carson, Nielen, Winzenburger, & Ess, 2012) (Table 2). At present, activation of mTOR has been recognized as a major event that causes AD pathogenesis (Yates, Zafar, Hubbard, Nagy, & Durant, 2013).…”