Phosphorylation of the AMPA receptor GluA1 subunit regulates memory load capacity.
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.
Institute of Genetics and Biophysics, CNR, Via P. Castellino 111, 80131, Naples, Italy.
Laura
L
Olivito
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Paola
P
Saccone
Dipartimento di Biologia e Biotecnologie, Università degli Studi di Roma "La Sapienza", Rome, Italy.|Centro di Ricerca in Neurobiologia-D. Bovet, Università degli Studi di Roma "La Sapienza", Rome, Italy.
Valentina
V
Perri
Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Hunterian 1001, 725 North Wolfe Street, Baltimore, MD, 21205, USA.
Julia L
JL
Bachman
Istituto di Biologia e Patologia Molecolare, CNR, Rome, Italy.
Paola
P
Fragapane
Dipartimento di Biologia e Biotecnologie, Università degli Studi di Roma "La Sapienza", Rome, Italy.|Centro di Ricerca in Neurobiologia-D. Bovet, Università degli Studi di Roma "La Sapienza", Rome, Italy.
Andrea
A
Mele
Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Hunterian 1001, 725 North Wolfe Street, Baltimore, MD, 21205, USA.
Richard L
RL
Huganir
Institute of Genetics and Biophysics, CNR, Via P. Castellino 111, 80131, Naples, Italy. deleonibus@igb.cnr.it.|Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. deleonibus@igb.cnr.it.
Elvira
E
De Leonibus
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004192:Discrimination, Psychological; D019706:Excitatory Postsynaptic Potentials; D005106:Exploratory Behavior; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D012694:Serine; D013997:Time Factors
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017868:Cyclic AMP-Dependent Protein Kinases; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D012694:Serine
AMPA-receptors phosphorylation; Hippocampus; Long-term memory; Protein kinases; Working memory capacity