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Quantifying Spontaneous Ca2+ Fluxes and their Downstream Effects in Primary Mouse Midbrain Neurons
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Published on: September 9, 2020

Nitric oxide applications prior and simultaneous to potentially excitotoxic NMDA-evoked calcium transients: cell

Aileen Schröter1, Shaida A Andrabi, Gerald Wolf

  • 1Institute for Medical Neurobiology, Otto-von-Guericke University, Leipziger Str. 44, D-39120 Magdeburg, Germany.

Brain Research
|October 4, 2005
PubMed

Insights

Nitric oxide (NO) shows dual effects on brain cells. Pre-exposure protects neurons from glutamate excitotoxicity, while co-exposure with glutamate potentiates damaging calcium influx, impacting neurodegenerative disease research.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) is a signaling molecule implicated in both neuroprotective and neurotoxic pathways.
  • Excitotoxicity, often mediated by glutamate receptor overactivation, is a key factor in neuronal damage and neurodegenerative diseases.
  • Intracellular calcium ([Ca2+]i) dynamics are critical in neuronal function and excitotoxicity.

Purpose of the Study:

  • To investigate the differential effects of nitric oxide (NO) on glutamate-induced intracellular calcium ([Ca2+]i) dynamics in mouse striatal neurons.
  • To determine if NO pre- or co-exposure modulates NMDA receptor-mediated excitotoxicity and neuronal survival.

Main Methods:

  • Mouse striatal neurons were stimulated with NMDA (N-methyl-D-aspartate) to induce excitotoxicity.
  • Neurons were exposed to an NO donor (SNAP) either before (pre-treatment) or during (co-treatment) NMDA stimulation.
  • Intracellular calcium ([Ca2+]i) dynamics were measured using the fluo-4 dye; cell death was assessed via Annexin V/propidium iodide staining; mitochondrial membrane potential was monitored using TMRM.

Main Results:

  • NO pre-treatment significantly reduced NMDA-evoked [Ca2+]i rises and protected neurons from NMDA-induced cell death.
  • NO co-treatment with NMDA potentiated [Ca2+]i rises, prolonging transients and increasing plateau levels, indicating excitotoxicity.
  • The mitochondrial permeability transition pore (mtPTP) blocker cyclosporin A prevented [Ca2+]i deregulation during NO/NMDA co-treatment, which was associated with decreased mitochondrial membrane potential.

Conclusions:

  • Nitric oxide exhibits dual roles in neuronal response to excitotoxicity: preconditioning confers protection, whereas acute co-exposure can be detrimental.
  • The detrimental effects of NO co-exposure appear linked to mitochondrial dysfunction and calcium dysregulation.
  • These findings offer insights into the complex role of NO in neurodegenerative processes involving glutamate excitotoxicity and calcium homeostasis.

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