Alterations in both cholinergic and glutamatergic systems have been suggested to contribute to the deficit in memory functions occurring during normal aging and related diseases. Nevertheless, the relative role of each component remains an open issue. In fact, the effect of glutamate on acetylcholine (ACh)-mediated responses is well documented. On the contrary, less is known about a cholinergic influence on responses induced by glutamate receptor activation. In the present study, we studied the effects of lesioning the cholinergic septohippocampal fibres with the immunotoxin 192 IgG-saporin on the synaptic responses mediated by glutamate in area CA1 of rat hippocampus. Concomitantly, these responses were recorded in aged animals to better assess the consequences of the cholinergic deficit in these animals.Experiments were conducted in 3-4-month-old and 25-33-month-old male Sprague-Dawley rats, as well as in young rats treated with an intraventricular injection of 192 IgG-saporin (4 μg in 7.5 μL of saline). One animal was daily studied using extracellular recordings in the ex vivo slice (400 μm) preparation. The composition of the bath medium was (mM): NaCl, 119; KCl, 3; MgSO 4 , 1.5; CaCl 2 3; NaHCO 3 , 26.2; NaH 2 PO 4 , 1.0; glucose, 11. Extracellular recordings were obtained from the apical dendritic layer of the CA1 hippocampal area using micropipettes filled with 2 M NaCl and having resistances of 2-6 MΩ. Presynaptic fibre volleys (PFVs) and field EPSPs (fEPSPs) were evoked by electrical stimulation (100 μs duration) of CA1 afferent fibres (Schaffer collaterals and commissural fibres) located in the stratum radiatum.Input-output (I/O) curves were first studied in control medium in young (10 slices in five animals), 192 IgG-saporin pretreated (11 slices in three animals) and aged rats (seven slices in five animals). Stimulation of the stratum radiatum induced a PFV followed by a fEPSP, both increasing with the stimulus intensity. The fEPSPs were totally suppressed by CNQX (10 μM) thus reflecting the activation of non-N-methyl-D-aspartate receptors (non-NMDAr). The comparison of the I/O curves revealed that the PFV were not significantly altered in young and 192 IgG-saporin pretreated animals [F(1,20) = 1.55, P = 0.23] as well as in young and aged rats [F(1,15) = 1.754, P = 0.2]. However, when the fEPSP slopes were plotted against the slope of the PFVs, we found that the non-NMDAr-mediated responses were not statistically affected in rats with the cholinergic denervation of the hippocampus [F(1,20) = 5.87, P = 0.17]. On the contrary, fEPSPs were significantly depressed in aged animals [F(1,15) = 6.229, P = 0.02].In another sets of experiments, I/O curves were constructed from slices perfused for at least 40 min with a Mg 2 + -free medium and where CNQX was added 20 min before the recordings. In these conditions, a fEPSP was induced which differed from that recorded in control medium by its slow onset, its prolonged duration and its sensitivity to 2-APV (30 μM). Comparison of the NMDAr-mediated synaptic responses revealed that both the amplitude [F(1,25) = 42.3, P < 0.0001] and the duration [F(1,25) = 5.87, P = 0.023] of NMDAr-mediated fEPSPs were significantly increased in 192 IgG-saporin pretreated rats. In aged rats, we found that the duration of these responses was significantly enhanced [F(1,28) = 5.08, P = 0.03] whereas the amplitude was not statistically altered [F(1,29) = 0.001, P = 0.97].The present study first did not reveal significant alterations of non-NMDAr-mediated synaptic responses of CA1 pyramidal cells after lesion of cholinergic septohippocampal fibres by the immunotoxin 192 IgG-saporin. These responses were significantly depressed in aged rats. These results therefore indicate that the cholinergic deficit occurring in the aged hippocampus do not significantly contribute to the impaired activation of these glutamate subtypes of receptors. Accordingly, this impairment was suggested to result mainly from a decreased number of synaptic contacts between glutamatergic afferents and pyramidal cells. On the other hand, we found that synaptic responses mediated by activation of NMDAr were significantly increased both in amplitude and duration in rats pretreated by 192 IgG-saporin as we previously reported with the use of intracellular recordings. Because the presynaptic fibre volley was not altered in these animals, this enhanced NMDAr mediated responses might not be due to a sprouting of glutamatergic fibres in response to the loss of cholinergic afferences. In addition, it might result from an impaired activation of cholinergic heteroreceptors presynaptically localized on glutamatergic terminals inhibiting glutamate release. However, this hypothesis predicts a parallel increase in non-NMDAr responses and we found that these responses were not affected. Finally, an increase in NMDAr binding sites seemed unlikely because it was reported to be unaffected or even decreased after cholinergic deafferentation by 192 IgG-saporin. In view of these results, we suggest that the increase in NMDAr activation induced by the cholinergic denervation may rather reflect changes in the gating properties of associated channels as supported by the significant increase in the duration of these glutamatergic responses. Interestingly, we found that the amplitude of NMDAr mediated responses was not altered in aged animals despite the assumption of fewer synaptic contacts between glutamatergic afferent fibres and pyramidal cells in these animals suggesting the occurrence of compensatory mechanisms. Considering the increased NMDAr activation recorded in the cholinergic deafferented hippocampus of 192 IgG-saporin pretreated rats, we may hypothesize that the age-related cholinergic deficit may be one possible mechanism of this compensation.In conclusion, this study shows that in CA1 hippocampal area: i) the glutamatergic neurotransmission is differentially affected by the cholinergic denervation depending on the glutamate subtype of receptors; and ii) the age-related cholinergic deficit may facilitate NMDAr activation and consequently synaptic plasticity in aged animals.