title: Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex.
abstract: Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing.
authors.affiliation: San Raffaele Scientific Institute, Milan, Italy. cambiaghi.marco@hsr.it
authors.forename: Marco
authors.initials: M
authors.lastname: Cambiaghi
authors.forename: Marco
authors.initials: M
authors.lastname: Cursi
authors.forename: Laura
authors.initials: L
authors.lastname: Magri
authors.forename: Valerio
authors.initials: V
authors.lastname: Castoldi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Fabio
authors.initials: F
authors.lastname: Minicucci
authors.forename: Rossella
authors.initials: R
authors.lastname: Galli
authors.forename: Letizia
authors.initials: L
authors.lastname: Leocani
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020123:Sirolimus / Q000008:administration & dosage*; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D020123:Sirolimus