Confirmation of Decreased Rates of Cerebral Protein Synthesis In Vivo in a Mouse Model of Tuberous Sclerosis Complex

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Tuberous sclerosis complex (TSC) is an autosomal dominant disorder associated with intellectual disability and autism spectrum disorder in approximately 50% of patients.
• Mutations in TSC1 and TSC2 genes lead to the inhibition of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway.
• The mTORC1 pathway regulates mRNA translation, and it is hypothesized that TSC-related mutations upregulate this pathway, increasing protein synthesis.

Purpose of the Study:

• To investigate in vivo protein synthesis rates in a second mouse model of TSC (Tsc2(Mjg)+/-).
• To examine mTORC1 signaling pathways under baseline conditions and following anesthesia.
• To assess the impact of prior isoflurane anesthesia on mTORC1 signaling and protein synthesis.

Main Methods:

• Utilized a Tsc2+/- mouse model (Tsc2(Mjg)+/-) with a different mutation locus.
• Measured in vivo protein synthesis rates in the brain.
• Analyzed mTORC1 signaling pathways, including effects of isoflurane anesthesia.

Main Results:

• Confirmed decreased in vivo rates of protein synthesis in the Tsc2(Mjg)+/- mouse model, consistent with previous findings.
• Demonstrated regionally selective effects of prior isoflurane anesthesia on mTORC1 signaling pathways.
• Results suggest a divergence from the central hypothesis regarding TSC and protein synthesis.

Conclusions:

• In vivo studies reveal decreased brain protein synthesis in TSC mouse models, challenging the prevailing hypothesis.
• Prior anesthesia can influence mTORC1 signaling pathways in a regionally selective manner.
• This research underscores the critical importance of in vivo investigations for understanding TSC pathophysiology.