Human molecular genetics

Intact neuronal function in Rheb1 mutant mice: implications for TORC1-based treatments.

PMID 25759467


Target of rapamycin complex 1 (TORC1) is an important regulator of neuronal function. However, whereas a modest activation of the TORC1 signaling pathway has been shown to affect synaptic plasticity, learning and memory, the effect of TORC1 hypo-activation is less clear. This knowledge is particularly important since TORC1 inhibitors may hold great promise for treating a variety of disorders, including developmental disorders, aging-related disorders, epilepsy and cancer. Such treatments are likely to be long lasting and could involve treating young children. Hence, it is pivotal that the effects of sustained TORC1 inhibition on brain development and cognitive function are determined. Here, we made use of constitutive and conditional Rheb1 mutant mice to study the effect of prolonged and specific reduction in the TORC1 pathway. We show that Rheb1 mutant mice show up to 75% reduction in TORC1 signaling, but develop normally and show intact synaptic plasticity and hippocampus-dependent learning and memory. We discuss our findings in light of current literature in which the effect of pharmacological inhibition of TORC1 is studied in the context of synaptic plasticity and learning. We conclude that in contrast to TORC1 hyper-activity, cognitive function is not very sensitive to sustained and specific down-regulation of TORC1 activity.