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Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor.

ABSTRACT: Nitric oxide (*NO) production in response to stimulation of the NMDA glutamate receptor is implicated not only in the synaptic plasticity in hippocampus but may also participate in excitotoxic cell death. Using *NO-selective microssensors inserted into the diffusional field of *NO in acute hippocampal slices, we describe the *NO concentration dynamics evoked by NMDA receptor activation and report profound differences along the trisynaptic loop of the hippocampus. We measured the oxygen gradient across the slice thickness and conclude that *NO measurements were performed at cell layers experiencing physiological oxygen tensions. Recordings performed at increasing distances from the point of NMDA receptor stimulation resulted in a progressive decrease of *NO signals, reaching undetectable levels for distances >400 microm, supporting the notion of a wide diffusional spread of endogenously generated *NO in the hippocampus. Neither a picoinjection nor a continuous perfusion of NMDA resulted in high steady-state *NO levels; rather all signals were transient, suggesting that cells are able to efficiently respond to high *NO concentrations (typically 200-400 nM) bringing it to very low nM levels; the claimed high micromolar *NO range achieved by excessive stimulation of NMDA receptor may have to be reevaluated. The distinct responses to NMDA receptor stimulation along the trysynaptic loop suggest a differential *NO activity and/or regulation among the hippocampal subregions. These findings may be relevant for the understanding of the role of *NO in physiologic mechanisms in the hippocampus and the differential sensitivity of the hippocampal subregions to NMDA receptor-dependent neurodegeneration.

SUBMITTER: Ledo A

PROVIDER: S-EPMC1297656 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor.

Ledo Ana A Barbosa Rui M RM Gerhardt Greg A GA Cadenas Enrique E Laranjinha João J

Proceedings of the National Academy of Sciences of the United States of America 20051117 48

Nitric oxide (*NO) production in response to stimulation of the NMDA glutamate receptor is implicated not only in the synaptic plasticity in hippocampus but may also participate in excitotoxic cell death. Using *NO-selective microssensors inserted into the diffusional field of *NO in acute hippocampal slices, we describe the *NO concentration dynamics evoked by NMDA receptor activation and report profound differences along the trisynaptic loop of the hippocampus. We measured the oxygen gradient ...[more]

PMID: 16293699

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Project description:HIV-associated neurocognitive disorders afflict about half of HIV-infected patients. HIV-infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors. Here, we show that Tat causes a time-dependent, biphasic change in NMDA-evoked increases in intracellular Ca(2+) concentration ([Ca(2+)]i). NMDA-evoked responses were potentiated following 2-h exposure to Tat (50 ng/mL). Tat-induced potentiation of NMDA-evoked increases in [Ca(2+)]i peaked by 8 h and then adapted by gradually reversing to baseline by 24 h and eventually dropping below control by 48 h. Tat-induced potentiation of NMDA-evoked responses was blocked by inhibition of lipoprotein receptor-related protein (LRP) or Src tyrosine kinase. Potentiation was unaffected by inhibition of nitric oxide synthase (NOS). However, NOS activity was required for adaptation. Adaptation was also prevented by inhibition of soluble guanylate cyclase (sGC) and cyclic guanosine monophosphate-dependent protein kinase G (PKG). Together, these findings indicate that Tat potentiates NMDA-evoked increases in [Ca(2+)]i via LRP-dependent activation of Src and that this potentiation adapts via activation of the NOS/sGC/PKG pathway. Adaptation may protect neurons from excessive Ca(2+) influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders. HIV-associated neurocognitive disorders (HAND) afflict about half of HIV-infected patients. HIV-infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors (NMDARs). We show that HIV-1 Tat evoked biphasic changes in NMDA-evoked [Ca(2+) ]i responses. Initially, Tat potentiated NMDA-evoked responses following LRP-mediated activation of Src kinase. Subsequently, Tat-induced NMDAR potentiation adapted by activation of a NOS/sGC/PKG pathway that attenuated NMDA-evoked increases in [Ca(2+)]i . Adaptation may be a novel neuroprotective mechanism to prevent excessive Ca(2+) influx. Solid and dashed arrows represent direct and potentially indirect connections, respectively.

Dataset Information

Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor.

Publications

Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor.

Similar Datasets

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