RESUMO
Coriandrum sativum L. (coriander), which is an annual herb of the Apiaceae family, has been traditionally used as a remedy. Here we tested whether heated extract of coriander leaf protects nigral dopaminergic neurodegeneration after exposure to 6-hydroxydopamine (6-OHDA). After injection of 6-OHDA into the rat substantia nigra pars compacta (SNpc), dopaminergic degeneration, which was determined by tyrosine hydroxylase immunostaining, was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that extracellular Zn2+ influx is involved in neurodegeneration. Both intracellular Zn2+ dysregulation determined by ZnAF-2 fluorescence and dopaminergic degeneration in the SNpc induced by 6-OHDA were rescued by co-injection of 0.25% coriander extract, which also reduced reactive oxygen species (ROS) production in the SNpc determined by aminophenyl fluorescein fluorescence. The present study suggests that coriander leaf extract protects nigral dopaminergic neurodegeneration induced by intracellular Zn2+ dysregulation. It is likely that the nutraceutical property of coriander leaf extract contributes to the protection via reducing ROS production.
Assuntos
Coriandrum , Animais , Oxidopamina/farmacologia , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de OxigênioRESUMO
Coriandrum sativum (coriander) is an annual herb of the Apiaceae family and has been used as a traditional remedy. Here we examined whether heated leaf extract of coriander decreases the concentrations of heavy metals in tissues. Male ddY mice were given a drinking water containing 0.25% of heated leaf extract of coriander for 8 weeks. Eight weeks after the intake, the concentrations of zinc, iron, copper, arsenic, and cadmium were measured in the liver and kidney. The intake of coriander did not modify the concentrations of all heavy metals tested in the liver, but decreased the concentrations of iron, arsenic, and cadmium in the kidney. Because heavy metals can induce oxidative stress, the effect of coriander intake on hydrogen peroxide-induced oxidative stress was compared between slices from the kidney and liver. The slices were immersed in Ringer solution containing 100 µM hydrogen peroxide and aminophenyl fluorescein (APF), a probe for detecting reactive oxygen species (ROS). APF fluorescence was markedly increased in the control kidney slices, while the increase was completely blocked in kidney slices from coriander intake group. In contrast, APF fluorescence was also markedly increased in the control liver slices, while the increase was not blocked by coriander intake. The present study indicates that intake of coriander leaf extract contributes to powerful resistance to oxidative stress in the kidney, probably via decreased concentrations in heavy metals. It is likely that decrease in arsenic concentration to the detection limit is a major factor for the resistance.
Assuntos
Coriandrum/química , Metais Pesados/análise , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Animais , Arsênio/análise , Arsênio/metabolismo , Cádmio/análise , Cádmio/metabolismo , Ferro/análise , Ferro/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metais Pesados/metabolismo , Camundongos , Extratos Vegetais/química , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Physiological significance of synaptic Zn2+ signaling was examined at perforant pathway-CA1 pyramidal cell synapses. In vivo long-term potentiation (LTP) at perforant pathway-CA1 pyramidal cell synapses was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. Perforant pathway LTP was not attenuated under perfusion with CaEDTA (10 mM), an extracellular Zn2+ chelator, but attenuated under perfusion with ZnAF-2DA (50 µM), an intracellular Zn2+ chelator, suggesting that intracellular Zn2+ signaling is required for perforant pathway LTP. Even in rat brain slices bathed in CaEDTA in ACSF, intracellular Zn2+ level, which was measured with intracellular ZnAF-2, was increased in the stratum lacunosum-moleculare where perforant pathway-CA1 pyramidal cell synapses were contained after tetanic stimulation. These results suggest that intracellular Zn2+ signaling, which originates in internal stores/proteins, is involved in LTP at perforant pathway-CA1 pyramidal cell synapses. Because the influx of extracellular Zn2+ , which originates in presynaptic Zn2+ release, is involved in LTP at Schaffer collateral-CA1 pyramidal cell synapses, synapse-dependent Zn2+ dynamics may be involved in plasticity of postsynaptic CA1 pyramidal cells.
Assuntos
Região CA1 Hipocampal/metabolismo , Potenciação de Longa Duração/fisiologia , Via Perfurante/metabolismo , Células Piramidais/metabolismo , Transmissão Sináptica/fisiologia , Zinco/metabolismo , Animais , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Sinapses/metabolismoRESUMO
Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer's disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency.
Assuntos
Transtorno Depressivo/psicologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Modelos Biológicos , Sistema Hipófise-Suprarrenal/fisiopatologia , Estresse Fisiológico , Zinco/deficiência , Animais , Transtorno Depressivo/etiologia , HumanosRESUMO
Glutamate excitotoxicity is involved in dopaminergic degeneration in the substantia nigra pars compacta (SNpc). Here we compared vulnerability to neurodegeneration after exposure to NMDA and AMPA. Apomorphine-induced movement disorder and dopaminergic degeneration in the SNpc, which are associated with Parkinson's syndrome, were induced after injection of AMPA into the SNpc of rats, but not after injection of NMDA. Co-injection of 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors rescued dopaminergic degeneration and increase in intracellular Zn2+ by AMPA. Furthermore, we tested the effect of capturing reactive oxygen species (ROS) produced by Zn2+ on neuroprotection in vivo. The levels of ROS, which were determined by HYDROP, a membrane-permeable H2O2 fluorescence probe and Aminophenyl Fluorescein (APF), a fluorescence probe for hydroxyl radical and peroxynitrite, were increased after injection of AMPA, but not after co-injection of CaEDTA, an extracellular Zn2+ chelator, suggesting that increase in Zn2+ influx by AMPA elevates the levels of intracellular ROS. AMPA-mediated dopaminergic degeneration was completely rescued by co-injection of either HYDROP or APF. The present study indicates that neurotoxic signaling of the influx of extracellular Zn2+ through Zn2+-permeable GluR2-lacking AMPA receptors is converted to ROS production and that capturing the ROS completely protects dopaminergic degeneration after exposure to AMPA, but not NMDA. It is likely that regulation of the conversion from Zn2+ influx into ROS production plays a key role to preventing Parkinson's syndrome.
Assuntos
Doença de Parkinson , Receptores de AMPA , Ratos , Animais , Espécies Reativas de Oxigênio/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Ratos Wistar , Peróxido de Hidrogênio , Zinco/metabolismo , Edema , Neurônios DopaminérgicosRESUMO
Parkinson's disease is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn2+ toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (H2O2) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn2+ level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular H2O2 produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, H2O2 signaling is not the case in the striatum. Paraquat-induced Zn2+ dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.
Assuntos
Paraquat , Canais de Cátion TRPM , Corpo Estriado/metabolismo , Dopamina , Neurônios Dopaminérgicos/metabolismo , Ácido Glutâmico , Peróxido de Hidrogênio , Paraquat/toxicidade , Substância Negra/metabolismo , Zinco/metabolismo , Zinco/toxicidadeRESUMO
To elucidate the mechanism and significance of 6-hydroxydopamine (6-OHDA)-induced Zn2+ toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (H2O2) produced by 6-OHDA is a trigger for intracellular Zn2+ dysregulation in the SNpc. Intracellular H2O2 level elevated by 6-OHDA in the SNpc was completely inhibited by co-injection of GBR 13069 dihydrochloride (GBR), a dopamine reuptake inhibitor, suggesting that 6-OHDA taken up through dopamine transporters produces H2O2 in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with H2O2, glutamate accumulated in the extracellular compartment and the accumulation was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) channels. In addition to 6-OHDA, H2O2 also induced intracellular Zn2+ dysregulation via AMPA receptor activation followed by nigral dopaminergic degeneration. Furthermore, 6-OHDA-induced nigral dopaminergic degeneration was completely inhibited by co-injection of either HYDROP, an intracellular H2O2 scavenger or GBR into the SNpc. The present study indicates that H2O2 is produced by 6-OHDA taken up through dopamine transporters in the SNpc, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via AMPA receptor activation, resulting in nigral dopaminergic degeneration prior to movement disorder. It is likely that intracellular H2O2, but not extracellular H2O2, is a key trigger for nigral dopaminergic degeneration via intracellular Zn2+ dysregulation.
Assuntos
Dopamina , Peróxido de Hidrogênio , Animais , Neurônios Dopaminérgicos , Oxidopamina/toxicidade , Ratos , Ratos Wistar , Substância Negra , ZincoRESUMO
On the basis of the evidence that extracellular Zn2+ influx induced with AMPA causes Parkinson's syndrome in rats that apomorphine-induced movement disorder emerges, here we used a low dose of AMPA, which does not increase intracellular Zn2+ level in the substantia nigra pars compacta (SNpc) of young adult rats, and tested whether intracellular Zn2+ dysregulation induced with AMPA is accelerated in the SNpc of aged rats, resulting in age-related vulnerability to Parkinson's syndrome. When AMPA (1 mM) was injected at the rate of 0.05 µl/min for 20 min into the SNpc, intracellular Zn2+ level was increased in the SNpc of aged rats followed by increase in turning behavior in response to apomorphine and nigral dopaminergic degeneration. In contrast, young adult rats do not show movement disorder and nigral dopaminergic degeneration, in addition to no increase in intracellular Zn2+. In aged rats, movement disorder and nigral dopaminergic degeneration were rescued by co-injection of either extracellular (CaEDTA) or intracellular (ZnAF-2DA) Zn2+ chelators. 1-Naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors blocked increase in intracellular Zn2+ in the SNpc of aged rats followed by rescuing nigral dopaminergic degeneration. The present study indicates that intracellular Zn2+ dysregulation is accelerated by Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation in the SNpc of aged rats, resulting in age-related vulnerability to Parkinson's syndrome.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Degeneração Neural , Doença de Parkinson Secundária/induzido quimicamente , Parte Compacta da Substância Negra/efeitos dos fármacos , Receptores de AMPA/agonistas , Zinco/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidade , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Masculino , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Parte Compacta da Substância Negra/fisiopatologia , Ratos Wistar , Receptores de AMPA/metabolismoRESUMO
Parkinson's disease (PD) is a progressive neurological disease characterized by a selective loss of nigrostriatal dopaminergic neurons. The exact cause of the neuronal loss remains unclear. Here, we report a unique mechanism of nigrostriatal dopaminergic neurodegeneration, in which extracellular Zn2+ influx plays a key role for PD pathogenesis induced with 6-hydroxydopamine (6-OHDA) in rats. 6-OHDA rapidly increased intracellular Zn2+ only in the substantia nigra pars compacta (SNpc) of brain slices and this increase was blocked in the presence of CaEDTA, an extracellular Zn2+ chelator, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, indicating that 6-OHDA rapidly increases extracellular Zn2+ influx via AMPA receptor activation in the SNpc. Extracellular Zn2+ concentration was decreased under in vivo SNpc perfusion with 6-OHDA and this decrease was blocked by co-perfusion with CNQX, supporting 6-OHDA-induced Zn2+ influx via AMPA receptor activation in the SNpc. Interestingly, both 6-OHDA-induced loss of nigrostriatal dopaminergic neurons and turning behavior to apomorphine were ameliorated by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Co-injection of TPEN into the SNpc blocked 6-OHDA-induced increase in intracellular Zn2+ but not in intracellular Ca2+. These results suggest that the rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation in the SNpc induces nigrostriatal dopaminergic neurodegeneration, resulting in 6-OHDA-induced PD in rats.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Espaço Extracelular/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Substância Negra/patologia , Zinco/metabolismo , Animais , Cálcio/metabolismo , Quelantes/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Etilenodiaminas , Espaço Intracelular/metabolismo , Masculino , Degeneração Neural/patologia , Oxidopamina , Ratos WistarRESUMO
The herbicide paraquat (PQ) has been reported to enhance the risk of developing Parkinson's disease (PD) from epidemiological studies. PQ-induced reactive oxygen species (ROS) are linked with a selective loss of nigrostriatal dopaminergic neurons. Here, we first report a unique mechanism of nigrostriatal dopaminergic degeneration, in which rapid intracellular Zn2+ dysregulation via PQ-induced ROS production causes PD in rats. When the substantia nigra pars compacta (SNpc) of rats was perfused with PQ, extracellular concentrations of glutamate and Zn2+ were increased and decreased, respectively, in the SNpc. These changes were ameliorated by co-perfusion with Trolox, an antioxidative agent. In in vitro slice experiments, PQ rapidly increased extracellular Zn2+ influx via AMPA receptor activation. Both loss of nigrostriatal dopaminergic neurons and increase in turning behavior in response to apomorphine were markedly reduced by coinjection of PQ and intracellular Zn2+ chelator, i.e., ZnAF-2DA into the SNpc. Furthermore, loss of nigrostriatal dopaminergic neurons induced with a low dose of PQ, which did not induce any behavioral abnormality, was completely blocked by coinjection of ZnAF-2DA. The present study indicates that rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation, which is initially induced by PQ-mediated ROS production in the SNpc, induces nigrostriatal dopaminergic degeneration, resulting in PQ-induced PD in rats. Intracellular Zn2+ dysregulation in dopaminergic neurons is the cause of PQ-induced pathogenesis in the SNpc, and the block of intracellular Zn2+ toxicity leads to defending PQ-induced pathogenesis.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Espaço Extracelular/metabolismo , Paraquat/toxicidade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Substância Negra/patologia , Zinco/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Quelantes/farmacologia , Quelantes/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Ácido Glutâmico/metabolismo , Masculino , Modelos Biológicos , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Substância Negra/efeitos dos fármacosRESUMO
On the basis of the evidence that paraquat (PQ)-induced extracellular Zn2+ influx causes PQ-induced pathogenesis in the substantia nigra pars compacta (SNpc) of rats, we postulated that the transient receptor potential melastatin 2 (TRPM2) cation channels activated with PQ-induced reactive oxygen species (ROS) are linked with extracellular glutamate accumulation in the SNpc, followed by age-related intracellular Zn2+ dysregulation. Presynaptic activity (glutamate exocytosis), which was determined with FM4-64, was enhanced in the SNpc after exposure to PQ, and the enhancement was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of TRPM2 cation channels, suggesting that PQ-induced ROS enhances presynaptic activity in the SNpc, probably via TRPM2 channel activation. Extracellular glutamate concentration in the SNpc was increased almost to the same extent under the SNpc perfusion with PQ of young and aged rats, and was suppressed by co-perfusion with ACA, suggesting that PQ-induced TRPM2 cation channel activation enhances glutamate exocytosis in the SNpc. Interestingly, PQ more markedly increased intracellular Zn2+ in the aged SNpc, which was also blocked by co-injection of ACA and CaEDTA, an extracellular Zn2+ chelator. Loss of nigrostriatal dopaminergic neurons was more severely increased in aged rats and completely blocked by co-injection of PQ and CaEDTA into the SNpc. The present study indicates that rapid influx of extracellular Zn2+ into dopaminergic neurons via PQ-induced TRPM2 cation channel activation accelerates nigrostriatal dopaminergic degeneration in aged rats. It is likely that vulnerability to PQ-induced pathogenesis in the aged SNpc is due to accelerated intracellular Zn2+ dysregulation.
Assuntos
Envelhecimento/patologia , Neurônios Dopaminérgicos/metabolismo , Espaço Extracelular/metabolismo , Paraquat/toxicidade , Doença de Parkinson/patologia , Substância Negra/patologia , Zinco/metabolismo , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Exocitose/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Masculino , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de AMPA/metabolismo , Fatores de Risco , Substância Negra/efeitos dos fármacosRESUMO
On the basis of the findings that the rapid influx of extracellular Zn2+ into nigral dopaminergic neurons causes dopaminergic neurodegeneration, here we report that AMPA causes movement disorder in rats. AMPA markedly increased turning behavior in response to apomorphine 1 and 2 weeks after AMPA injection into the substantia nigra pars compacta (SNpc), while AMPA-induced movement disorder was suppressed by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and TPEN, suggesting that AMPA-induced movement disorder is due to intracellular Zn2+ dysregulation. Furthermore, AMPA markedly induced loss of nigrostriatal dopaminergic neurons 2 weeks after AMPA injection into the SNpc, while AMPA-induced neurodegeneration was also suppressed in the SNpc and the striatum by co-injection of ZnAF-2DA and TPEN. AMPA rapidly increased nigral intracellular Zn2+ after AMPA injection into the SNpc and this increase was blocked by co-injection of TPEN. These results indicate that AMPA receptor activation rapidly increases influx of extracellular Zn2+ into nigral dopaminergic neurons and causes nigrostriatal dopaminergic neurodegeneration, resulting in movement disorder in rats. The evidence that AMPA-induced intracellular Zn2+ dysregulation causes movement disorder via nigrostriatal dopaminergic neurodegeneration suggests that AMPA receptors, probably Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors are potential targets for overcoming Parkinson's syndrome.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Líquido Extracelular/metabolismo , Substância Negra/metabolismo , Zinco/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidade , Animais , Quelantes/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Discinesia Induzida por Medicamentos/prevenção & controle , Líquido Extracelular/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Substância Negra/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagemRESUMO
Artificial cerebrospinal fluid (ACSF), i.e., brain extracellular medium, which includes Ca2+ and Mg2+, but not other divalent cations such as Zn2+, has been used for in vitro and in vivo experiments. The present study deals with the physiological significance of extracellular Zn2+ in ACSF. Spontaneous presynaptic activity is suppressed in the stratum lucidum of brain slices from young rats bathed in ACSF containing 10 nM ZnCl2, indicating that extracellular Zn2+ modifies hippocampal presynaptic activity. To examine the in vivo action of 10 nM ZnCl2 on long-term potentiation (LTP), the recording region was perfused using a recording electrode attached to a microdialysis probe. The magnitude of LTP was not modified in young rats by perfusion with ACSF containing 10 nM ZnCl2, compared to perfusion with ACSF without Zn2+, but attenuated by perfusion with ACSF containing 100 nM ZnCl2. Interestingly, the magnitude of LTP was not modified in aged rats even by perfusion with ACSF containing 100 nM ZnCl2, but enhanced by perfusion with ACSF containing 10 mM CaEDTA, an extracellular Zn2+ chelator. The present study indicates that the basal levels of extracellular Zn2+, which are in the range of low nanomolar concentrations, are critical for synaptic activity and perhaps increased age-dependently.