Membrane-tethered AKT kinase regulates basal synaptic transmission and early phase LTP expression by modulation of post-synaptic AMPA receptor level

Abstract

The serine/threonine kinase AKT/PKB plays a fundamental role in a wide variety of neuronal functions, including neuronal cell development, axonal growth, and synaptic plasticity. Multiple evidence link AKT signaling pathways to regulation of late phase long-term synaptic plasticity, synaptogenesis, and spinogenesis, as well as long-term memory formation. Nevertheless, the downstream effectors mediating the effects of AKT on early phase long-term potentiation (eLTP) are currently unknown. Here we report that using different regimes of pharmacological activation and inhibition of AKT activity in acute hippocampal slices, we found that AKT regulates the post-synaptic expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors affecting solely the expression of eLTP, with no effect on its induction and maintenance. We further show that both maintenance of basal synaptic activity and expression of eLTP require plasma membrane tethering by activated AKT and that basal synaptic activity may be regulated via the direct effects of AKT1 on the expression level of post-synaptic AMPA receptors bypassing the canonical AKT signaling. Finally, we establish that eLTP expression requires the involvement of both the canonical AKT signaling pathways and the direct effect of AKT1 on AMPA receptor activity/expression in the post-synaptic membrane. © 2016 Wiley Periodicals, Inc.

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

“…To confirm that AZD inhibited AKT activity despite the hyperphosphorylation of AKT, we examined AKT substrates and found significantly decreased phosphorylation levels of both GSK-3β, in a dose-dependent manner, and TSC2 ( Figure 3a,c,d ). Finally, the AKT1/2 inhibitor A6730 (10 mM) was recently found to reduce levels of the AMPA receptor subunit GluA2 ( Pen et al, 2016 ), but we found no reduction even with the highest concentration of AZD or MK ( Figure 3a,d ).…”

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

“…3a,c). Recently, the AKT1/2 inhibitor A6730 (10 mM) was found to reduce levels of the AMPA receptor subunit GluA2 20 , but we found no reduction even with the highest concentration of AZD or MK (Fig. 3a,d).…”

“…4c). Because AKT has been linked to AMPA and NMDA receptor function 20 , we first examined the effect of deleting single Akt isoforms on basal synaptic transmission, presynaptic plasticity and short-term LTP in area CA1. We found normal synaptic input/output curves (Supplementary Fig.…”

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

“…In synaptic tagging, a stimulus establishes molecular "tags" in active synapses that can then become further potentiated in L-LTP by associating with newly synthesized plasticity-related proteins. Kinases triggered during E-LTP are thought to contribute to L-LTP, such as MAPK (Thomas and Huganir, 2004), CaMKII (Ma et al, 2015), protein kinase B (Pen et al, 2016), phosphoinositide 3-kinase (Asrar et al, 2009), and protein kinase C (Jalil et al, 2015).…”