Adenosine A(2A) receptors are required for normal BDNF levels and BDNF-induced potentiation of synaptic transmission in the mouse hippocampus.

Brain-derived neurotrophic factor (BDNF), a member of neurotrophin family, enhances synaptic transmission and regulates neuronal proliferation and survival. Both BDNF and its tyrosine kinase receptors (TrkB) are highly expressed in the hippocampus, where an interaction with adenosine A(2A) receptors (A(2A)Rs) has been recently reported. In the present paper, we evaluated the role of A(2A)Rs in mediating functional effects of BDNF in hippocampus using A(2A)R knock-out (KO) mice. In hippocampal slices from WT mice, application of BDNF (10 ng/mL) increased the slope of excitatory post-synaptic field potentials (fEPSPs), an index of synaptic facilitation. This increase of fEPSP slope was abolished by the selective A(2A) antagonist ZM 241385. Similarly, genetic deletion of the A(2A)Rs abolished BDNF-induced increase of the fEPSP slope in slices from A(2A)R KO mice The reduced functional ability of BDNF in A(2A)R KO mice was correlated with the reduction in hippocampal BDNF levels. In agreement, the pharmacological blockade of A(2)Rs by systemic ZM 241385 significantly reduced BDNF levels in the hippocampus of normal mice. These results indicate that the tonic activation of A(2A)Rs is required for BDNF-induced potentiation of synaptic transmission and for sustaining a normal BDNF tone in the hippocampus.

Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease mice.

The effect of chronic treatment with the selective adenosine A2A receptor antagonist SCH 58261 on the behavioral and electrophysiological alterations typical of R6/2 mice (a transgenic mouse model of Huntington's disease, HD), has been studied. Starting from 5 weeks of age, R6/2 and wild type (WT) mice were treated daily with SCH 58261 (0.01 mg/kg i.p.) for 7 days. In the following weeks, the ability of mice to perform in the rotarod, plus maze and open field tests were evaluated. In addition, with electrophysiological experiments in corticostriatal slices we tested whether the well-known increased NMDA vulnerability of R6/2 mice was prevented by SCH 58261 treatment. We found that chronic treatment with SCH 58262: i) fully prevented the alterations in emotional/anxious responses displayed by R6/2 mice; ii) did not prevent the impairment in motor coordination; iii) abolished the increase in NMDA-induced toxicity observed in the striatum of HD mice. On balance, targeting A2A receptors seems to have some beneficial effects in HD even though, given the complexity of A2A receptor pharmacology and HD pathogenesis, further studies are necessary to clarify whether A2A receptor antagonists have therapeutic potential in HD.

Adenosine A(2A) receptors modulate BDNF both in normal conditions and in experimental models of Huntington's disease.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances synaptic transmission and regulates neuronal proliferation and survival. Functional interactions between adenosine A(2A) receptors (A(2A)Rs) and BDNF have been recently reported. In this article, we report some recent findings from our group showing that A(2A)Rs regulate both BDNF functions and levels in the brain. Whereas BDNF (10 ng/ml) increased the slope of excitatory postsynaptic field potentials (fEPSPs) in hippocampal slices from wild-type (WT) mice, it was completely ineffective in slices taken from A(2A)R knock-out (KO) mice. Furthermore, enzyme immunoassay studies showed a significant reduction in hippocampal BDNF levels in A(2A)R KO vs. WT mice. Having found an even marked reduction in the striatum of A(2A)R KO mice, and as both BDNF and A(2A)Rs have been implicated in the pathogenesis of Huntington's disease (HD), an inherited striatal neurodegenerative disease, we then evaluated whether the pharmacological blockade of A(2A)Rs could influence striatal levels of BDNF in an experimental model of HD-like striatal degeneration (quinolinic acid-lesioned rats) and in a transgenic mice model of HD (R6/2 mice). In both QA-lesioned rats and early symptomatic R6/2 mice (8 weeks), the systemic administration of the A(2A)R antagonist SCH58261 significantly reduced striatal BDNF levels. These results indicate that the presence and the tonic activation of A(2A)Rs are necessary to allow BDNF-induced potentiation of synaptic transmission and to sustain a normal BDNF tone. The possible functional consequences of reducing striatal BDNF levels in HD models need further investigation.

Is the functional interaction between adenosine A(2A) receptors and metabotropic glutamate 5 receptors a general mechanism in the brain? Differences and similarities between the striatum and the hippocampus.

The aim of the present paper was to examine, in a comparative way, the occurrence and the mechanisms of the interactions between adenosine A(2A) receptors (A(2A)Rs) and metabotropic glutamate 5 receptors (mGlu5Rs) in the hippocampus and the striatum. In rat hippocampal and corticostriatal slices, combined ineffective doses of the mGlu5R agonist 2-chloro-5-hydroxyphenylglycine (CHPG) and the A(2A)R agonist CGS 21680 synergistically reduced the slope of excitatory postsynaptic field potentials (fEPSPs) recorded in CA1 and the amplitude of field potentials (FPs) recorded in the dorsomedial striatum. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway appeared to be involved in the effects of CGS 21680 in corticostriatal but not in hippocampal slices. In both areas, a postsynaptic locus of interaction appeared more likely. N-methyl-D: -aspartate (NMDA) reduced the fEPSP slope and FP amplitude in hippocampal and corticostriatal slices, respectively. Such an effect was significantly potentiated by CHPG in both areas. Interestingly, the A(2A)R antagonist ZM 241385 significantly reduced the NMDA-potentiating effect of CHPG. In primary cultures of rat hippocampal and striatal neurons (ED 17, DIV 14), CHPG significantly potentiated NMDA-induced lactate dehydrogenase (LDH) release. Again, such an effect was prevented by ZM 241385. Our results show that A(2A) and mGlu5 receptors functionally interact both in the hippocampus and in the striatum, even though different mechanisms seem to be involved in the two areas. The ability of A(2A)Rs to control mGlu5R-dependent effects may thus be a general feature of A(2A)Rs in different brain regions (irrespective of their density) and may represent an additional target for the development of therapeutic strategies against neurological disorders.

Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: a possible key mechanism in the modulation of N-methyl-D-aspartate effects.

Hippocampal metabotropic glutamate 5 receptors (mGlu5Rs) regulate both physiological and pathological responses to glutamate. Because mGlu5R activation enhances NMDA-mediated effects, and given the role played by NMDA receptors in synaptic plasticity and excitotoxicity, modulating mGlu5R may influence both the physiological and the pathological effects elicited by NMDA receptor stimulation. We evaluated whether adenosine A2A receptors (A(2A)Rs) modulated mGlu5R-dependent effects in the hippocampus, as they do in the striatum. Co-application of the A(2A)R agonist CGS 21680 with the mGlu5R agonist (RS)-2-chloro-s-hydroxyphenylglycine(CHPG) synergistically reduced field excitatory postsynaptic potentials in the CA1 area of rat hippocampal slices. Endogenous tone at A(2A)Rs seemed to be required to enable mGlu5R-mediated effects, as the ability of CHPG to potentiate NMDA effects was antagonized by the selective A(2A)R antagonist ZM 241385 in rat hippocampal slices and cultured hippocampal neurons, and abolished in the hippocampus of A(2A)R knockout mice. Evidence for the interaction between A(2A)Rs and mGlu5Rs was further strengthened by demonstrating their co-localization in hippocampal synapses. This is the first evidence showing that hippocampal A(2A)Rs and mGlu5Rs are co-located and act synergistically, and that A(2A)Rs play a permissive role in mGlu5R receptor-mediated potentiation of NMDA effects in the hippocampus.

Curcumin treatment protects rat retinal neurons against excitotoxicity: effect on N-methyl-D: -aspartate-induced intracellular Ca(2+) increase.

Curcumin, an extract from the plant Curcuma longa with well-known antioxidant and anti-inflammatory activities, was tested as protective agent against excitotoxicity in rat retinal cultures. A 24 h-treatment with curcumin reduced N-methyl-D: -aspartate (NMDA)-mediated excitotoxic cell damage, estimated as decrease of cell viability and increase in apoptosis. The protection was associated with decrease of NMDA receptor-mediated Ca(2+) rise and reduction in the level of phosphorylated NR1 subunit of the NMDA receptor. These results enlighten a new pharmacological action of the plant extract, possibly mediated by a modulation of NMDA receptor activity.

Permissive role of adenosine A2A receptors on metabotropic glutamate receptor 5 (mGluR5)-mediated effects in the striatum.

The metabotropic glutamate receptors 5 (mGlu5Rs) and the adenosine A2A receptors (A2ARs) have been reported to functionally interact in the striatum. The aim of the present work was to verify the hypothesis that the state of activation of A2A Rs could influence mGlu5R-mediated effects in the striatum. In electrophysiological experiments (extracellular recording in rat corticostriatal slices), the ability of the selective mGlu5R agonist CHPG to potentiate the reduction of the field potential amplitude induced by NMDA was prevented not only by the selective mGlu5R antagonist MPEP, but also by the selective A2AR antagonist ZM 241385. Analogously, the application of CHPG potentiated NMDA-induced toxicity (measured by LDH release) in cultured striatal neurons, an effect that was abolished by both MPEP and ZM 241385. Finally, the A2AR agonist CGS 21680 potentiated CHGP effects, an action that was reproduced and abolished, respectively, by forskolin (an activator of the cAMP/protein kinase A, PKA, pathway) and KT 5720 (a PKA inhibitor). The results indicate that A2ARs exert a permissive role on mGlu5R-induced effects in the striatum. Such an interaction may represent an additional target for the development of therapeutic strategies towards striatal disorders.

Modulation of glutamate release and excitotoxicity by adenosine A2A receptors.

Because an increased glutamate outflow is thought to play a crucial role in triggering excitotoxic neuronal death, drugs able to regulate glutamate release could be effective for the management of neurodegenerative diseases. In this article, the authors discuss the hypothesis that adenosine A2A receptor antagonists (A2A antagonists) may belong to the aforementioned category. In rats bilaterally lesioned with the excitotoxin quinolinic acid (QA) in the striatum, the A2A antagonist SCH 58261 significantly reduced the motor, EEG, and neuropathologic changes induced by the lesion. Such effects of SCH 58261 occurred only at low doses and were paralleled by an inhibition of QA-stimulated glutamate release. The role played by A2A antagonists in the regulation of glutamate outflow was also confirmed by preliminary results obtained in the model of paired-pulse stimulation in corticostriatal slices. Conversely, based on data obtained in cultured striatal neurons, A2A antagonists appear unable to directly inhibit NMDA effects. In conclusion, A2A antagonists show clear neuroprotective effects in models of brain injury, although their actual therapeutic potential needs to be confirmed in a wider range of doses and in models of neurodegenerative diseases in which presynaptic and postsynaptic effects play different relative roles.

The presence of astrocytes enhances beta amyloid-induced neurotoxicity in hippocampal cell cultures.

A characteristic feature of neuritic plaques in Alzheimer's disease is represented by the presence of activated astrocytes, surrounding dystrophic neurons and beta-amyloid deposition. To explore the role of astrocytes in in vitro beta-amyloid neurotoxicity, we studied the effect of beta-amyloid treatment in hippocampal neurons in two different cell models: pure cultures, where neurons were grown in absence of astrocytes and mixed cultures, where neurons were seeded on a confluent layer of astrocytes. We evaluated two characteristic aspects of in vitro beta-amyloid neurotoxicity: reduction of cell viability and degeneration of the neuritic tree. We demonstrated that neurons growing on astrocytes were more prone to the detrimental effect of the amyloid peptide, with respect to neurons grown in absence of the glial component. Our results support the hypothesis that beta-amyloid-astrocyte interaction can adversely condition neurons and contribute to neuronal damage in Alzheimer's disease.

Astrocytes contribute to neuronal impairment in beta A toxicity increasing apoptosis in rat hippocampal neurons.

Astrocytosis is a common feature of amyloid plaques, the hallmark of Alzheimer's disease (AD), along with activated microglia, neurofibrillary tangles, and beta-amyloid (beta A) deposition. However, the relationship between astrocytosis and neurodegeneration remains unclear. To assess whether beta A-stimulated astrocytes can damage neurons and contribute to beta A neurotoxicity, we studied the effects of beta A treatment in astrocytic/neuronal co-cultures, obtained from rat embryonic brain tissue. We found that in neuronal cultures conditioned by beta A-treated astrocytes, but not directly in contact with beta A, the number of apoptotic cells increased, doubling the values of controls. In astrocytes, beta A did not cause astrocytic cell death, nor did produce changes in nitric oxide or prostaglandin E(2) levels. In contrast, S-100 beta expression was remarkably increased. Our data show for the first time that beta A--astrocytic interaction produces a detrimental effect on neurons, which may contribute to neurodegeneration in AD.

Age-related decline in the functional response of striatal group I mGlu receptors.

In order to verify whether striatal group I metabotropic glutamate (mGlu) receptors undergo functional alteration in ageing, the effects induced by the selective agonist 3,5-dihydroxyphenylglycine (DHPG) in the striatum of young (3 months) and aged (24-25 months old) rats were compared. The ability of DHPG to stimulate phosphoinositide (PI) hydrolysis (striatal slices), to influence striatal dopamine release (in vivo microdialysis) and to potentiate the effects of NMDA on extracellular field potential amplitude (extracellular recordings on striatal slices) was reduced in the striatum of old vs young rats. These results show an age-dependent reduction in the functional response of striatal group I mGlu receptors, which may be one of the factors underlying the reduced ability aged striatum to integrate information.

Two distinct forms of long-term depression coexist at the mossy fiber-CA3 synapse in the hippocampus during development.

During a critical period of postnatal development, between postnatal days 6 and 14, a high-frequency stimulation train (100 Hz for 1 s) to the mossy fibers induces a long-term depression (LTD) of synaptic efficacy of 29 +/- 5.2%. This form of LTD is homosynaptic. It is independent of the activation of N-methyl-D-aspartate or metabotropic glutamate receptors but needs an increase in calcium into the postsynaptic cell for its induction. At the same synapse LTD also could be induced by low-frequency stimulation of the mossy fibers (1 Hz for 15 min). In this case the magnitude of the depression is 37 +/- 4.2%. This form of LTD is N-methyl-D-aspartate independent but requires the activation of metabotropic glutamate receptors because it is prevented by (S)-alpha-methyl-4-carboxyphenylglycine (1 mM). Moreover its induction appears to be presynaptic, because, in contrast with the high-frequency one, it is not blocked by loading the postsynaptic cell with the calcium chelator EGTA or bis-(-o-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid (BAPTA). Saturation of one form of LTD does not occlude the other, suggesting that high and low frequency-induced LTD depend on distinct mechanisms of induction and expression. Quantal (noise deconvolution) analysis of minimal excitatory postsynaptic potentials shows, similarly to high-frequency LTD, a decrease in quantal content without any change in quantal size after low-frequency LTD, suggesting that in both forms of LTD the site where maintenance mechanisms are located is presynaptic.

Reduced hippocampal in vitro CA1 long-term potentiation in rat offsprings with increased circulating corticosterone during neonatal life.

A moderate increase in plasma level of corticosterone was induced in dams by adding the hormone (200 micrograms/ml) to the drinking water from the day after delivery to weaning. This procedure produces a parallel increase in plasma levels of the hormone in the pups (from 0.7 +/- 0.1 to 1.2 +/- 0.2 micrograms/100 ml) at 10 days of lactation. A significant (P < 0.01) reduction in the magnitude of the long-term potentiation (LTP) of the CA1 population spike occurred in hippocampal slices obtained from 30-45 day old male corticosterone-nursed rats with respect to controls, while no significant difference occurred in the magnitude of the basal CA1 evoked extracellular somatic field potentials with respect to controls. The results demonstrate that a moderate increase in plasma corticosterone during neonatal life, obtained through maternal milk, has long-lasting effects on the hippocampal CA1 synaptic plasticity. In addition, these results together with our previous findings [Catalani, A. et al., Brain Res., 624 (1993) 209-215], demonstrating that 30 day old corticosterone-nursed offsprings perform better than controls in the place learning version of the Morris water maze, show no relationships between in vitro CA1 LTP induction and spatial learning in agreement with literature data.

In vitro hippocampal dentate frequency potentiation induction as model to detect electrophysiological correlates of some cognitive impairments in striatally-lesioned rats.

1. Hippocampal frequency potentiation, a form of short-term potentiation of hippocampal electrical synaptic potentials that is related to mnemonic and learning processes, is typically damped in aged rats and in certain rat strains with impaired place learning performance. 2. In vitro induction of hippocampal dentate frequency potentiation has been found decreased in striatally-lesioned rats with impaired place learning performance in water maze test. 3. The results demonstrate that also in brain-lesioned rats the poor performances in place learning of the animals are associated with a selective dentate frequency potentiation impairment. Thus in vitro induction of dentate frequency potentiation might be regarded as a model to detect the electrophysiological counterpart of the cognitive impairment in rats with altered place learning.

Block by N6-L-phenylisopropyl-adenosine of the electrophysiological and morphological correlates of hippocampal ischaemic injury in the gerbil.

1. The effects of the mixed A1 and A2 adenosine receptor agonist N6-L-phenyl-isopropyladenosine (L-PIA) were tested on ischaemia-induced hippocampal neuronal injury in gerbils subjected to 5-min bilateral carotid occlusion. For comparison, the effects of the selective A2 adenosine receptor agonist, CGS 21680 were tested. 2. Five-min bilateral carotid occlusion produced within 1 week an irreversible suppression of the CA1, but not of the dentate extracellular electrical somatic responses, in 30% of gerbil hippocampal slices with respect to controls. In addition, a significant reduction occurred in the density of CA1 hippocampal pyramidal neurones but not of dentate granule cells with respect to controls. 3. Injection 1 h before or after bilateral carotid occlusion of L-PIA (0.8-1.5 mg kg-1, i.p.) but not of CGS 21680 (5 mg kg-1, i.p.), significantly prevented the irreversible disappearance of the CA1 extracellular electrical somatic responses with respect to controls. In addition, the CA1 pyramidal neuronal loss was also prevented. 4. The results show that activation of A1 adenosine receptors is able to prevent or block the electrophysiological and morphological correlates of hippocampal neuronal injury after global ischaemia in the gerbil, suggesting that adenosine receptor agonists might have a useful role in the treatment of neuronal functional and anatomical injury due to ischaemia.

Effects of felbamate, kynurenic acid derivatives and NMDA antagonists on in vitro kainate-induced epileptiform activity.

The effects of the novel anticonvulsant felbamate, which binds to the 5-7 dichlorokynurenic binding sites, were tested towards the CA1 epileptiform activity induced in rat hippocampal slices by kainic acid. The effects of the kynurenic acid derivatives 7-chlorokynurenic acid and 5-7 dichlorokynurenic acid and of the NMDA antagonists CGS 19755, MK-801 and ketamine were also studied for comparison. Slice perfusion with 1 microM kainic acid produced within 30 min the development of an evoked CA1 epileptiform bursting made up by an increase in amplitude of the primary population spikes followed by the appearance of secondary epileptiform population spikes. Slice perfusion with CGS 19755 (100 microM) or MK-801 (100 microM) or ketamine (100 microM) failed to affect within 30 min the CA1 epileptiform activity due to kainic acid. On the contrary, slice perfusion with felbamate (1.3-1.6 mM) or 7-chlorokynurenic acid (100 microM) or 5-7-dichlorokynurenic acid (100 microM) produced within 30 min a significative (p < 0.05) decrease of the kainate-induced epileptiform bursting duration. The results indicate that felbamate and kynurenic acid derivatives but not NMDA antagonists present an inhibitory effect against the epileptiform activity due to kainic acid.

Selective opposite modulation of dentate granule cells excitability by mu and kappa opioids in rat hippocampal slices.

The effects of opioids having affinity for kappa (U50,488H and U54,494A) and mu receptors (DAMGO and methadone) were tested on the excitability of the dentate and CA1 neurons in rat hippocampal slices. Slice perfusion with 25 microM U50,488H or with 12 microM U54,494A produced within 60 min a significant (P < 0.05) decrease in the amplitude of the primary dentate population spike (PS). A similar decrease occurred on the CA1 PS amplitude only at concentrations higher than 100 microM of U50,488H or 50 microM of U54,494A. Slice perfusion with 0.5 microM DAMGO, or 100 microM methadone produced an increase in the amplitude of the primary dentate and CA1 PS and the appearance of secondary PSs. Slice perfusion with 12 microM U50,488H or with 25 microM of methadone significantly (P < 0.05) decreased or increased, respectively, the rate of appearance of the dentate posttetanic potentiation (PTP) and long-term potentiation (LTP) after a 100 Hz tetanic stimulation of the perforant path. The same concentration of U50,488H or methadone did not affect the rate of appearance of the CA1 PTP and LTP after a 100 Hz tetanic stimulation of the Schaffer collaterals. The data, providing evidence for a selective opposite modulation by mu and kappa opioids on the basal and stimulated dentate neuronal excitability, indicate the dentate area as a target within the hippocampus for an opposite influence between mu and kappa opioids on neuronal excitability.

Glutamate-dependent mechanisms in the induction of a calcium long-term potentiation-like phenomenon.

The electric synaptic efficacy, in terms of extracellular electrical potentials, and the intracellular postsynaptic efficacy, in terms of inositol phosphate (IP) accumulation, were evaluated in rat hippocampal slices exposed for a brief period (10 min) to a high concentration of calcium (+2.7 mM). In addition, the effects of N-methyl-D-asparate (NMDA) ionotropic and metabotropic glutamate receptor (mGluR) antagonists on the induction and the establishment or maintenance of enhanced synaptic efficacy of CA1 pyramidal neurons due to high-calcium exposure were also tested. Elevation of the calcium concentration from 1.3-4 mM in the medium bathing hippocampal slices produced a long-lasting (80 over 90 min) increase in the slope of the CA1 somatic excitatory postsynaptic potential and the amplitude of the population spike (PS). Slice perfusion with NMDA antagonists cyclazocine and cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755) or with mGluR antagonists L-2-amino-3-phosphonopropionic acid (AP3) or alpha-methyl-4-carboxyphenyl-glycine (all 0.1 mM), during the 10-min period of exposure to high-calcium prevented the induction of such changes. By contrast, slice perfusion with the same concentration of CGS 19755 or L-AP3 did not affect the already established long-lasting increase in amplitude of CA1 PS induced by high-calcium. Moreover, high-calcium failed to produce any significant modification of the basal IP accumulation or of the IP accumulation elicited by mGluR agonist 1S,3R-trans-amino cyclo-pentane-1,3-dicarboxylic acid (ACPD). In conclusion, the results confirm that high-calcium induces a long-lasting increase in synaptic efficacy in rat hippocampal slices. Both NMDA ionotropic and mGluR receptors are involved in the induction, but not in the maintenance, of this phenomenon. In line with these data no modifications of basal or ACPD-induced phosphoinositide hydrolysis have been found during the maintenance stage.

7-chlorokynurenic acid prevents in vitro epileptiform and neurotoxic effects due to kainic acid.

1. The effects of 7-chlorokynurenic acid were studied against the epileptiform and neurotoxic effects due to the non-NMDA excitatory amino acid, kainic acid, in rat hippocampal slices. 2. Slice perfusion with 7-chlorokynurenic acid (100 microM), significantly (p < 0.05) decreased the duration of the CA1 epileptiform bursting due to 1 microM kainic acid. 3. Slice perfusion with 7-chlorokynurenic acid (100 microM) significantly (p < 0.05) increased the probability of recovery of the CA1 population spike after a neurotoxic concentration (12 microM) of kainic acid. 4. The results indicate that 7-chlorokynurenic acid affects, with a similar potency, epileptiform and neurotoxic effects due to kainic acid.

Reduced hippocampal CA1 Ca(2+)-induced long-term potentiation is associated with age-dependent impairment of spatial learning.

Expression of Ca(2+)-induced CA1 long-term potentiation (LTP) was analysed in hippocampal slices obtained from (1) 3-month-old and (2) 18-20-month-old Sprague-Dawley rats selected for their performances in the Morris water maze task. In all slices, a transient (10 min) increase of extracellular Ca2+ concentration (4 mM) caused a long-lasting enhancement of potentials evoked by electrical stimulation of radiatum fibers. However, a significant difference was found in the degree of potentiation among groups. In particular, increases of the CA1 response amplitudes were significantly lower in old rats impaired in spatial learning than in young at 30 (P < 0.05), 60, 90 and 120 min (P < 0.01) after restoring the normal Ca2+ concentration. On the contrary, no differences were observed between young animals and the old ones with good performances in spatial learning. The data suggest that amplitude of CA1 Ca(2+)-induced LTP in old rats is related to spatial learning abilities.