Phosphorylation of the AMPA receptor GluA1 subunit regulates memory load capacity

Abstract

Memory capacity (MC) refers to the number of elements one can maintain for a short retention interval. The molecular mechanisms underlying MC are unexplored. We have recently reported that mice as well as humans have a limited MC, which is reduced by hippocampal lesions. Here, we addressed the molecular mechanisms supporting MC. GluA1 AMPA-receptors (AMPA-R) mediate the majority of fast excitatory synaptic transmission in the brain and are critically involved in memory. Phosphorylation of GluA1 at serine residues S831 and S845 is promoted by CaMKII and PKA, respectively, and regulates AMPA-R function in memory duration. We hypothesized that AMPA-R phosphorylation may also be a key plastic process for supporting MC because it occurs in a few minutes, and potentiates AMPA-R ion channel function. Here, we show that knock-in mutant mice that specifically lack both of S845 and S831 phosphorylation sites on the GluA1 subunit had reduced MC in two different behavioral tasks specifically designed to assess MC in mice. This demonstrated a causal link between AMPA-R phosphorylation and MC. We then showed that information load regulates AMPA-R phosphorylation within the hippocampus, and that an overload condition associated with impaired memory is paralleled by a lack of AMPA-R phosphorylation. Accordingly, we showed that in conditions of high load, but not of low load, the pharmacological inhibition of the NMDA–CaMKII–PKA pathways within the hippocampus prevents memory as well as associated AMPA-R phosphorylation. These data provide the first identified molecular mechanism that regulates MC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-014-0927-1) contains supplementary material, which is available to authorized users.

β‐adrenergic‐mediated dynamic augmentation of sarcolemmal CaV1.2 clustering and co‐operativity in ventricular myocytes

“…Additionally, in neurons, [Ca 2+ ] i and more specifically, influx of Ca 2+ through Ca V 1.2 channels, is considered to regulate Ca V 1.2 channel trafficking and endocytosis to tune excitability there (Green et al, 2007;Hall et al, 2013). Furthermore, phosphorylation of the AMPAR subunit GluA1 at Ser 845 by PKA and/or calcium/calmodulin-dependent protein kinase II, or PKC at Ser 831 , promotes plasma membrane insertion of the receptors, facilitating long-term potentiation by increasing channel P o and homeostatic scaling up (Makino et al, 2011;Diering et al, 2016;Olivito et al, 2016). Conversely, dephosphorylation by calcineurin leads to receptor internalization, long-term depression and homeostatic scaling down (Lee et al, 1998).…”

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…The role of the GluA1 subunit in learning and memory processes has been the most extensively investigated (Guntupalli et al., 2016; Hanley, 2008; Hsieh et al., 2006). The GluA1 subunit has several phosphorylation sites on its intracellular carboxy terminus (including Ser818, Ser831, and Ser845), and many of these sites are involved in the regulation of AMPARs at the synapse (Olivito et al., 2016). For example, phosphorylation at Ser831 and Ser845 regulates the conductivity of the ion channel and the translocation of the AMPAR to the surface membrane, respectively (Olivito et al., 2016).…”

“…The GluA1 subunit has several phosphorylation sites on its intracellular carboxy terminus (including Ser818, Ser831, and Ser845), and many of these sites are involved in the regulation of AMPARs at the synapse (Olivito et al., 2016). For example, phosphorylation at Ser831 and Ser845 regulates the conductivity of the ion channel and the translocation of the AMPAR to the surface membrane, respectively (Olivito et al., 2016). In an interesting manner, recent studies revealed that GluA1‐dependent synaptic transmission is impaired in AD, although its involvement in memory and cognitive process in AD remains unknown (Hsieh et al., 2006).…”

Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: another understanding of ketamine CNS toxicity

“…GluA1, one of the subunits of AMPA receptor and its intracellular phosphorylation sites (S845 and S831) play a key role in hippocampal activity-dependent synaptic trafficking of AMPA receptor, which is of vital importance for learning and memory343536. We determined the hippocampal post-synaptic membrane protein levels of GluA1, p-S845 and p-S831.…”