Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

Abstract

The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum-and amino acidstarved cells have reported that glutamine addition can either stimulate or repress mTORC1 activity, depending on the particular experimental system that was used. However, these experiments do not directly address the effect of glutamine on mTORC1 activity under physiological conditions in nondeprived cells in vivo. We present experimental results indicating that intrahippocampal administration of glutamine to rats reduces mTORC1 activity. Moreover, post-training administration of glutamine impairs long-term spatial memory formation, while coadministration of glutamine with leucine had no influence on memory. Intracellular recordings in hippocampal slices showed that glutamine did not alter either excitatory or inhibitory synaptic activity, suggesting that the observed memory impairments may not result from conversion of glutamine to either glutamate or GABA. Taken together, these findings indicate that glutamine can decrease mTORC1 activity in the brain and may have implications for treatments of neurological diseases associated with high mTORC1 signaling.

Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice

“…Thus there is a strong evidence for beneficial effects of mTOR inhibition in AD, in increasing life span in diverse set of animals (Ehninger, et al, 2014, Johnson, et al, 2013). Contrary to this beneficial effects, the rapamycin or genetic disruption of mTOR has shown to block long-term potentiation and memory functions in vitro and intact animals (Rozas, et al, 2015, Stoica, et al, 2011, Sui, et al, 2008, Tang, et al, 2002). Thus biological effects of mTOR inhibition are diverse and often have opposite effects based on the model or the mTOR regulator studied.…”