A study upon short term and long term memory mechanisms

Memory can be subdivided in short term and long term memory. Short term memory formation can be established by covalent modifications of pre-existing proteins while long term memory requires protein synthesis, in particular in the synaptodendritic compartment. The mammalian target of rapamycin (mTOR) regulates protein translation and thus cell growth, proliferation, survival and synaptic plasticity. Here we examined the effect of rapamycin (RAPA), scopolamine and mecamilamine on short and long term memory using a step-down inhibitory avoidance task, performing recall at 1, 4 and 24 h after acquisition in adult Wistar rats. RAPA (3 nml/10 μl) was injected icv 30 min before acquisition trial. This time was chosen on the basis of the diffusion kinetics of the drug obtained using MALDI-TOF-TOF profiling which showed that RAPA diffused from the injection site to the hippocampus within 20 and 40 min after icv injection, thus ensuring that RAPA was present in the hippocampus during the acquisition trial. Acquisition (AL) and recall (RL) latencies to step down the platform were measured. Vehicle treated rats acquired the behaviour, as shown by the significantly longer RL than AL at 1 and 4 h (both for short term memory) and 24 h (long term memory) after acquisition. A significant increase of mTOR activation was present in CA1 and CA3 pyramidal neurons at 1 h (+95%) and 4 h (+114%) but not at 24 h (+28%, ns) after acquisition. RAPA did not affect short term memory 1 and 4 h after acquisition. RAPA impaired long term memory, as shown by the significantly shorter RL at 24 h, and the significantly inhibited mTOR activation in CA1 and CA3 pyramidal neurons 4 h after acquisition. A significant increase of p70S6K activation was present in CA1 and CA3 neurons at 4 and 24 h after acquisition. The non selective muscarinic antagonist scopolamine (1.5 mg/kg, ip) introduced 30 min before acquisition impaired short term at 1 and 4 h but not long term memory encoding but increased mTOR activation in CA1 and in CA3 1 h after acquisition. The non selective nicotinic antagonist mecamylamine (15 nmol/5 μl, icv) given 10 min before scopolamine completely blocked mTOR activation at 1 h after step down acquisition. Our data demonstrate that mTOR and p70S6K activation are responsible for long term memory formation in the hippocampus. These results also support the idea that the cholinergic system, through muscarinic receptors, is involved in mTOR-independent short term memory, while through nicotinic receptors it activates mTOR, possibly leading to long term memory encoding. Taken together these date give strenght to the hypothesis that distinct molecular mechanisms are at the basis of the two different forms of memory.