Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice.

Mice carrying mutated human APPswe and PS1 (A246E) transgenes (A/P mice) show age-dependent memory impairment in hippocampus-dependent tasks. Moreover, the mice show normal learning in the water maze within a day but impairment across days. We recorded LTP in a slice preparation (CA1) and in chronically implanted animals (dentate gyrus, or DG) at 17-18 months of age. The genotypes did not differ in the basal synaptic transmission. Also, LTP induction and its maintenance over 60 min did not differ between A/P and control mice. However, the fEPSP enhancement in vivo decayed to 77% of its maximum in 24 h in A/P mice while remaining at 96% in control mice. The time course of the LTP decay in the A/P mice corresponds to their behavioral impairment and indicates that Abeta accumulation in the dentate gyrus may interfere with the signal transduction pathways responsible for memory consolidation.

Effects of D-cycloserine, a positive modulator of N-methyl-D-aspartate receptors, and ST 587, a putative alpha-1 adrenergic agonist, individually and in combination, on the non-delayed and delayed foraging behaviour of rats assessed in the radial arm maze.

The present study investigated whether alpha-1 adrenergic and glutamatergic N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms interact in memory processes, by examining the effects of individual and combined systemic administration of ST 587, a putative alpha-1 agonist, and D-cycloserine (DCS), a partial agonist at the glycine-B binding site of the NMDA receptor, on the performance of rats in non-delayed and delayed (4-6 h) foraging behaviour in the radial arm maze task, using the delayed non-matching to sample (DNMTS) version. The results indicated that DCS (5.0 mg/kg) decreased working memory errors, i.e. the number of re-entries into the previously visited arms during the sampling phase. In addition, both ST 587 (100 microg/kg) and DCS (10 mg/kg), when administered alone 30 min before a sampling phase, improved retention of this task as reflected by the increased number of correct choices before the first error during the retention phase. The combined administration of ST 587 and DCS, however, did not lead to better retention in the DNMTS task compared with the administration of each of the drugs alone. Combinations of sub-threshold doses of ST 587 (50 or 75 microg/kg) and DCS (5.0 or 7.5 mg/kg) also did not improve retention in this task. DCS (5.0 or 7.5 mg/kg) increased activity as indicated by the increased number of arm entries in a given time during the sampling phase. These findings suggest that the systemic administration of a positive modulator of the NMDA receptor facilitates hippocampal-dependent memory functions, but that these effects are not enhanced by combined administration with an alpha-1 agonist, even though the alpha-1 agonist is effective when given alone. The results support the idea that NMDA receptors modulate both mnemonic and non-mnemonic functions in the brain.

Minor role for alpha1-adrenoceptors in the facilitation of induction and early maintenance of long-term potentiation in the CA1 field of the hippocampus.

The influences of noradrenaline on the modulation of learning and memory functions, as well as synaptic plasticity, e.g., long-term potentiation (LTP), via beta-adrenoceptors are well documented, whereas the role of alpha1-adrenoceptors has not been studied extensively. Therefore, the effects of alpha1-agonists (ST 587 and methoxamine) on the induction of LTP were examined in the CA1 area of the hippocampus in vitro. Submaximal LTP in extracellular excitatory postsynaptic potentials (EPSP) was induced with theta burst stimulation using 4 bursts. The effects of a beta-agonist, isoproterenol, on synaptic potentiation were studied as a comparison in this preparation. At a concentration of 1 microM, ST 587 slightly increased the magnitude of potentiation in EPSPs (measured 30 min after stimulation) compared to a control pathway potentiated 30 min before drug infusion, whereas a lower concentration (0.3 microM) was not effective. Methoxamine did not induce any increase in the amount of submaximal LTP at concentrations of 0.3, 1.0, or 3.0 microM. Isoproterenol (1.5 microM) increased the amount of LTP when measured 30 min after stimulation, and also transiently increased synaptic transmission, measured both in the slope and amplitude of the field EPSP in the prepotentiated control pathway. Thus, the present results indicate that (1) alpha1-adrenoceptors have only a minor role in hippocampal synaptic plasticity in the CA1 area, but (2) the synaptic plasticity in the CA1 area of the hippocampus assessed by induction and early maintenance of LTP in vitro can be modulated through beta-adrenoceptors.

Preserved induction of long-term potentiation in the stratum radiatum in the CA1 field of hippocampal slices from transgenic mice overexpressing ornithine decarboxylase and overproducing putrescine.

The role of putrescine in synaptic neurotransmission and plasticity was studied using transgenic mice overexpressing ornithine decarboxylase (ODC), a polyamine-synthesizing enzyme. Transgenic mice were produced using the standard microinjection technique leading to elevated levels of putrescine in the periphery and in the brain. The experiments investigated whether or not ODC mice with elevated levels of putrescine show alterations in synaptic transmission and induction of long-term potentiation in the CA1 field of the hippocampus in vitro. Our results indicated that (1) putrescine levels in brain slices of the transgenic mice were more than ten times higher than those in fresh slices of control mice, although the absolute levels of putrescine and spermine decreased (by 15 and 40%, respectively) after 3-6 h incubation in vitro, while the levels of spermidine slightly increased (by 10%), (2) the excitatory synaptic response waveforms were wider (an increased half-width), and paired-pulse facilitation was somewhat reduced in ODC mice as compared to controls, and (3) potentiation of excitatory synaptic responses (measured 30-45 min after theta burst stimulation) did not differ between ODC and control mice. These results indicate that synaptic transmission is affected, but synaptic plasticity in the field CA1 assessed in vitro is not changed by elevated levels of intracellular putrescine.

Enhancement of intermediate-term memory by an alpha-1 agonist or a partial agonist at the glycine site of the NMDA receptor.

The aim of the present study was to investigate whether the activation of alpha-1 adrenergic receptors can influence intermediate-term memory. Therefore, the effects of ST 587 (30 or 100 micrograms/kg), a putative alpha-1 agonist, on the retention of the radial arm task using non-matching to sample with a 4-h delay were investigated in rats. The results indicated that the administration of ST 587 (100 micrograms/kg) before a sampling phase increased the time to complete the sampling phase which was due to an increased number of errors of repetition (regarded as working memory errors) and a reduced number of arms visited in a given time (regarded as behavioral activity). However, this treatment increased the number of correct choices before the first error during the retention phase in this task. Since we were also interested in investigating the role of NMDA receptors in memory encoding, we investigated whether NMDA receptor modulation by d-cycloserine (1 or 10 mg/kg), a partial agonist of the glycine site on the NMDA receptor, had any influence on the performance of rats in this task. The results indicated that d-cycloserine (10 mg/kg) given before the sampling phase did not influence the performance of rats during the sampling phase, but it did improve their choice accuracy during the retention phase of this task. These data suggest that the systemic administration of either an alpha-1 agonist or an indirect agonist of NMDA receptors can facilitate intermediate-term retention of spatial information.