Changes in intracellular pH associated with glutamate excitotoxicity

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Excitotoxic neuronal injury is linked to increased cytosolic calcium.
• The role of other intracellular ions, like hydrogen ions, in glutamate-induced neuronal death is unclear.

Purpose of the Study:

• To investigate the association between intracellular hydrogen ion concentration and glutamate-induced neuronal death.
• To explore the dynamics of intracellular pH (pHi) during and after toxic glutamate exposure.

Main Methods:

• Cultured hippocampal neurons were used to measure intracellular hydrogen ion concentrations with the fluorescent dye BCECF.
• Neurons were exposed to glutamate (GLU), elevated external potassium (K+), or sodium (Na+) removal.
• Inhibitors of intracellular pH regulation were employed to assess their impact on pHi recovery.

Main Results:

• Glutamate exposure induced initial cytosolic acidification, followed by a rebound alkalinization.
• Reduced extracellular calcium attenuated the initial GLU-induced acidification.
• Inhibitors of pH regulation and sodium removal slowed pHi recovery from GLU-induced acidification.
• Prolonged glutamate exposure led to a progressive increase in intracellular hydrogen ions, indicating delayed neuronal damage.

Conclusions:

• Intracellular acidification, particularly the delayed progressive increase, may contribute to excitotoxic neuronal death.
• Cytosolic acidification may act synergistically with calcium influx to mediate excitotoxicity.
• These findings highlight the critical role of intracellular pH regulation in neuronal survival following excitotoxic insults.