ABSTRACT
Title
Protein translation inhibition impairs long term memory
Authors
D. Lana
DOTTORATO DI RICERCA IN FARMACOLOGIA, TOSSICOLOGIA E TRATTAMENTI INNOVATIVI - XXVI CICLO (DOTTORATO INTERNAZIONALE), AFFERENTE ALLA SCUOLA DI DOTTORATO BIOMEDICA, CON SEDE AMMINISTRATIVA PRESSO IL DIPARTIMENTO DI FARMACOLOGIA PRECLINICA E CLINICA “MARIO AIAZZI MANCINI”, sede consorziata presso Università Paul Sabatier, Tolosa, Francia
Affiliazione : Dipartimento di Farmacologia Preclinica e Clinica "Mario Aiazzi Mancini", Università di Firenze
Viale Pieraccini 6, 50139 Firenze
DOTTORATO DI RICERCA IN FARMACOLOGIA, TOSSICOLOGIA E TRATTAMENTI INNOVATIVI - XXVI CICLO (DOTTORATO INTERNAZIONALE), AFFERENTE ALLA SCUOLA DI DOTTORATO BIOMEDICA, CON SEDE AMMINISTRATIVA PRESSO IL DIPARTIMENTO DI FARMACOLOGIA PRECLINICA E CLINICA “MARIO AIAZZI MANCINI”, sede consorziata presso Università Paul Sabatier, Tolosa, Francia
Affiliazione : Dipartimento di Farmacologia Preclinica e Clinica "Mario Aiazzi Mancini", Università di Firenze
Viale Pieraccini 6, 50139 Firenze
Abstract
Memory can be subdivided in short term and long term memory (1). Short term memory can be established by covalent modifications of pre-existing proteins (2) while long term memory requires protein synthesis, in particular in the synaptodendritic compartment (3). The mammalian target of rapamycin (mTOR) regulates protein translation and thus cell growth, proliferation, survival and synaptic plasticity(4). Here we examined the effect of rapamycin (RAPA) and scopolamine on short and long term memory using a step-down inhibitory avoidance task, performing recall 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 diffusion kinetics of the drug obtained using MALDI-TOF-TOF profiling which showed that RAPA diffused from the injection site to the hippocampus within 20-40 min after icv injection, thus ensuring that RAPA was already present in the hippocampus during the acquisition trial. Acquisition (AL) and recall (RL) latencies to step down the platform were measured. AL was not different between vehicle and RAPA treated rats. Animals treated with vehicle acquired the behaviour, as shown by RL that was significantly longer than AL at 1 and 4 h (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%; P<0.01) and 4 h (+114%; P<0.001) but not at 24 h (+28%, not significant) after acquisition. RAPA did not affect short term memory 1 and 4 h after acquisition (RL: controls: 297.3±2 sec; RAPA treated rats at 1 h 243± 8, at 4 h 240±33 sec; n.s.). RAPA impaired long term memory, as shown by the significantly shorter RL at 24 h after acquisition (RAPA treated rats: 182±34 sec, P<0.05 vs controls). RAPA significantly inhibited mTOR activation in CA1 and CA3 pyramidal neurons. Statistical analysis (two-way ANOVA) showed that RAPA significantly modified mTOR activation in CA1 (Treatment: F1,21=7.62, P<0.05; Time: F3,21=8.87, P<0.001; TreatmentxTime: F3,21=10.46, P<0.001) and CA3 (Treatment: F1,23=29.49, P<0.0001; Time: F3,23=59.93, P<0.0001; TreatmentxTime: F3,78=4.99, P<0.01) at 4 h after acquisition. A significant increase of p70S6K activation was present in CA1 and CA3 neurons at 4 and 24 h after acquisition. RAPA treatment significantly inhibited p70S6K activation. Statistical analysis (two-way ANOVA) showed that RAPA significantly modified p70S6K activation in CA1 (Treatment: F1,23=29.49, P<0.01; Time: F3,23=59.93, P<0.05; TreatmentxTime: F3,78=4.99, P<0.05) and CA3 (Treatment: F1,23=25.49, P<0.01; Time: F3,23=40.93, P<0.05; TreatmentxTime: F3,78=4.26, P<0.01) at 24 h after acquisition. The non selective muscarinic antagonist scopolamine (1.5 mg/kg, ip) 30 min before acquisition impaired short term but not long term memory encoding (Treatment: F1,59=13.54, P<0,0001; Time: F3,59=59.60, P<0,0001; TreatmentxTime: F3,59=11.47, P<0.0001). We found that scopolamine increased mTOR activation in CA1 1 h after acquisition (Treatment: F1,33=10.37, P<0,001; Time: F3,33=59.19, P<0,0001; TreatmentxTime: F3,33=7.15, P<0.05) and in CA3 at 1, 4 and 24 h after acquisition (Treatment: F1,41=25.42, P<0,0001; Time: F3,41=29.12, P<0,0001; TreatmentxTime: F3,41=25.42, P<0.0001). Our data demonstrate that mTOR and p70S6K activation are responsible for long term memory formation in the hippocampus. These results support the idea (5) that the cholinergic system is involved in short term but not long term memory encoding. Taken together these data give strenght to the hypothesis that distinct molecular mechanisms are at the basis of the two different forms of memory.
1) McGaugh JL (2000) - Science vol 287, 248
2) Kandel ER (2001) - Science vol 294, 1030
3) Bailey CH et al. (2004) - Neuron vol 44, 49
4) Martin DE and Hall MN (2005) - Curr Opin Cell Biol vol 17, 158
5) Pazzagli A, Pepeu G (1964) - Int J Pharmacol vol 4, 291
1) McGaugh JL (2000) - Science vol 287, 248
2) Kandel ER (2001) - Science vol 294, 1030
3) Bailey CH et al. (2004) - Neuron vol 44, 49
4) Martin DE and Hall MN (2005) - Curr Opin Cell Biol vol 17, 158
5) Pazzagli A, Pepeu G (1964) - Int J Pharmacol vol 4, 291