Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity

Abstract

Protein synthesis is required for the expression of enduring memories and long-lasting synaptic plasticity. During cellular proliferation and growth, S6 kinases (S6Ks) are activated and coordinate the synthesis of de novo proteins. We hypothesized that protein synthesis mediated by S6Ks is critical for the manifestation of learning, memory, and synaptic plasticity. We have tested this hypothesis with genetically engineered mice deficient for either S6K1 or S6K2. We have found that S6K1-deficient mice express an early-onset contextual fear memory deficit within one hour of training, a deficit in conditioned taste aversion (CTA), impaired Morris water maze acquisition, and hypoactive exploratory behavior. In contrast, S6K2-deficient mice exhibit decreased contextual fear memory seven days after training, a reduction in latent inhibition of CTA, and normal spatial learning in the Morris water maze. Surprisingly, neither S6K1-nor S6K2-deficient mice exhibited alterations in protein synthesis-dependent late-phase long-term potentiation (L-LTP). However, removal of S6K1, but not S6K2, compromised early-phase LTP expression. Furthermore, we observed that S6K1-deficient mice have elevated basal levels of Akt phosphorylation, which is further elevated following induction of L-LTP. Taken together, our findings demonstrate that removal of S6K1 leads to a distinct array of behavioral and synaptic plasticity phenotypes that are not mirrored by the removal of S6K2. Our observations suggest that neither gene by itself is required for L-LTP but instead may be required for other types of synaptic plasticity required for cognitive processing.

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

“…Zitzmann et al (2013) showed that the lower concentration of Hsp90 inhibitors induced p70S6K signaling correlated with stimulation of compensatory pathways. Furthermore, p70S6K-deficient mice had distinct impacts on learning, memory, and hippocampal synaptic plasticity with a compromised hippocampal LTP (Antion et al 2008). We found that hippocampal p70S6K level suppressed following Aβ injection that was prevented by GA pretreatment, concurrent with improvement in PA memory.…”

Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage

“…12). Moreover, mice lacking either the mTORC1 negative regulator Tsc2 or the downstream targets 4e-bp2 and S6k1/2 exhibit altered synaptic plasticity and memory (13)(14)(15). However, several aspects of these results are controversial.…”

“…S1). Sixth, mice lacking the mTORC1 downstream target S6k1 or S6k2 exhibit normal L-LTP, suggesting that S6Ks do not control mTORC1 mediated-translation of mRNAs that underlie L-LTP (13). It is also noteworthy that mice lacking S6ks only exhibit very subtle memory phenotypes (13).…”

Haloperidol Regulates the State of Phosphorylation of Ribosomal Protein S6 via Activation of PKA and Phosphorylation of DARPP-32

“…Knock-in mice expressing a mutated form of DARPP-32, in which Thr34 is replaced by Ala (DARPP-32 T34A mutant mice), and Gnal + /À (Ga olf ) heterozygous mice were generated as described in previous studies (Belluscio et al, 1998;Svenningsson et al, 2003) and were backcrossed for at least 10 generations on a C57BL/6 background. S6K1 knockout mice were generated via direct gene replacement with a neomycin cassette (previously described in Shima et al (1998) and were then outcrossed as described in Antion et al (2008). Animals were maintained in a 12-h light-dark cycle, in stable conditions of temperature (221C), with food and water ad libitum.…”

“…S6K-dependent phosphorylation of rpS6 has an important role in the control of cell size (Pende et al, 2004;Ruvinsky et al, 2005) and protein synthesis-dependent plasticity, such as long-term potentiation (Antion et al, 2008). In addition, phosphorylation at Ser235/236 has been proposed to promote protein synthesis by facilitating rpS6 recruitment to the 5 0 cap complex, during the formation of the preinitiation translation complex (Roux et al, 2007).…”