Effects of pharmacological inhibition of dopamine receptors on memory load capacity.

Memory capacity (MC) refers to the limited capacity of working memory and is defined as the number of elements that an individual can remember for a short retention interval. MC is impaired in many human pathologies, such as schizophrenia and ageing. Fronto-striatal dopamine regulates working memory, through its action on dopamine D1- and D2-like receptors. Human and rodent studies have suggested that MC is improved by D2 dopamine receptor agonists. Although D1 receptors have been crucially involved in the maintenance of working memory during delay, their role in regulating the capacity of WM remains poorly explored. In this study, we tested the effects of systemic injection of the D1-like and D2-like receptor antagonists, SCH 23390 and Haloperidol respectively, on MC in mice. For this, we used a modified version of the object recognition task, the Different/Identical Objects Task (DOT/IOT), which allows the evaluation of MC in rodents. The results showed a negative interaction between the dose of both drugs and the number of objects that could be remembered. The doses of SCH 23390 and Haloperidol that impaired novel object discrimination in the highest memory load condition were about 4 and 3 time lower, respectively, of those impairing performance in the lowest memory load condition. However, while SCH 23390 specifically impaired memory load capacity, the effects of Haloperidol were associated to impairment in exploratory behaviors. These findings may help to predict the cognitive side effects induced by Haloperidol in healthy subjects.

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.