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

Abstract

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.

Rheb in neuronal degeneration, regeneration, and connectivity

“…These data further assess that even though the upregulation of mTORC1 pathway is highly sensitive and leads to cognitive defects as seen in TSC, the sustained suppression of mTORC1 using drugs like rapamycin may not affect the memory and learning significantly (Goorden et al, 2015).…”

“…However, in conditional adult Rheb knockout mice even though a reduction in the downstream effectors like S6K and 4E-BP1 phosphorylation was observed (Weatherill et al, 2010;Goorden et al, 2015), the hippocampal LTP, learning and memory was not effected to a larger extend (Goorden et al, 2015). This indicates that even a mild activation of the mTORC1 signaling can bring about a drastic effect on synaptic plasticity and learning associated with various diseases (Lim and Crino, 2013), while a mild inhibition of mTORC1 appears not to affect memory functions (Goorden et al, 2015).…”

“…This indicates that even a mild activation of the mTORC1 signaling can bring about a drastic effect on synaptic plasticity and learning associated with various diseases (Lim and Crino, 2013), while a mild inhibition of mTORC1 appears not to affect memory functions (Goorden et al, 2015). This is in accordance with the need to use high concentrations of rapamycin for impairing learning and plasticity in mice (Gkogkas et al, 2010;Goorden et al, 2015). The relative non-responsiveness in the synaptic plasticity by reduction of Rheb may also be due to the existence of Rheb2, which also activates mTORC1 (Tee et al, 2005).…”

“…Specific deletion of the mTORC1 component Raptor, in the neuronal progenitors, leads to decreased brain size in the developing embryos due to impaired cell cycle progression and increased apoptosis . Moreover, Rheb knockout mice are embryonically lethal (Goorden et al, 2011(Goorden et al, , 2015. Conditional Rheb knockout in adult mice leads to limited life span of the animals indicating altogether, that Rheb is essential for embryonic as well as adult animal survival (Goorden et al, 2011(Goorden et al, , 2015.…”

“…The reduction of mTORC1 activity in specific regions of adult brain affects learning, memory and social behavior (Angliker et al, 2015;Goorden et al, 2015).…”