Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2

Abstract

Mutations in the TSC1 or TSC2 tumor suppressor genes lead to tuberous sclerosis complex (TSC), a dominant hamartomatous disorder that often presents with mental retardation, epilepsy and autism. The etiology of these neurological symptoms is unclear and the function of the TSC pathway in neurons is unknown. We found that in post-mitotic, hippocampal pyramidal neurons of mice and rats, loss of Tsc1 or Tsc2 triggered enlargement of somas and dendritic spines and altered the properties of glutamatergic synapses. Furthermore, loss of a single copy of the Tsc1 gene was sufficient to perturb dendritic spine structure. Morphological changes required regulation of the actin-depolymerization factor cofilin at a conserved LIM-kinase phosphorylation site, the phosphorylation of which was increased by loss of Tsc2. Thus, the TSC pathway regulates growth and synapse function in neurons, and perturbations of neuronal structure and function are likely to contribute to the pathogenesis of the neurological symptoms of TSC.

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

“…Indeed, no morphological effects were observed following a 24 hour exposure to rapamycin although previous studies clearly demonstrate alterations in cell morphology following more prolonged rapamycin treatment (Tavazoie et al, 2005).…”

“…Recent evidence suggests that loss of function mutations in the tuberous sclerosis complex genes (TSC1 and TSC2) leads to constitutive activation of the mTOR cascade (Arrazola et al, 2002;Inoki et al, 2002;Kenerson et al, 2002;Onda et al, 2002, Tee et al, 2002, El-Hashemite et al, 2003 and disturbs the regulation of neuronal morphology and function mediated by TSC1 and TSC2 (Tavazoie et al, 2005) resulting in abnormal neuronal organization and seizures (Uhlmann et al, 2002). Rapamycin has been proposed as a treatment modality for tuberous sclerosis complex (TSC), a multisystem, autosomal dominant disorder characterized by abnormal brain development, epilepsy, and potentially life threatening disorders such as pulmonary lymphangioleimyomatosis (Johnson and Tattersfield, 2002;Crino et al, 2006) Rapamycin is a potent translational modifier in neurons although its effects on gene transcription and neuronal development are poorly understood.…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…In addition (as discussed above) an excitatory action of GABA has been reported in TSC [162]. Mouse models of TSC point to additional mechanisms that would support seizure generation, such as abnormal glutamate homeostasis, increased α-amino-3-hydroxy-5-methyl-4-isixazolepropionic acidreceptor-mediated currents, impaired astrocytic gap junction coupling, and potassium buffering [221,225,226].…”

Advances in behavioral genetics: mouse models of autism

“…216 The brains of these animals also have smaller ventricles and thinner white matter tracts connecting the corpus callosum. 217 In mouse models of tuberous sclerosis, the conditional loss of Tsc1 leads to abnormal dendritic spine morphology and density, 218 enhanced cortical excitability, 219 enlarged neurons in the cortex and hippocampus, and seizures. 220 The altered excitation state of cortex in the Tsc1 conditional null mouse is not associated with tuber formation or changes in distribution of GAD67, used as a marker for GABAergic function.…”