Na+ channel expression and neuronal function in the Na+/H+ exchanger 1 null mutant mouse

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mice lacking sodium-hydrogen exchanger 1 (NHE1) experience early death and recurrent seizures.
• Previous studies indicated increased neuronal excitability and sodium current density in hippocampal CA1 neurons of NHE1-deficient mice.
• The underlying mechanisms, specifically concerning sodium channel expression and regulation, remained unclear.

Purpose of the Study:

• To investigate if increased excitability in NHE1-deficient mice is confined to CA1 neurons.
• To determine if elevated sodium current density results from altered sodium channel expression.
• To identify specific sodium channel subtypes that are upregulated in these mice.

Main Methods:

• Neurophysiological recordings to assess neuronal excitability and sodium current density.
• Autoradiography and immunoblotting techniques to quantify sodium channel expression.
• Comparative analysis between NHE1-deficient and wild-type mice.

Main Results:

• Both hippocampal CA1 and cortical neurons showed increased membrane excitability and sodium current density.
• Sodium channel density was selectively upregulated in the hippocampus and cortex (P < 0.05).
• Sodium channel subtype I expression increased in the hippocampus, while subtype II increased in the cortex.

Conclusions:

• Mice lacking NHE1 exhibit selective upregulation of sodium channel expression in hippocampal and cortical regions.
• This upregulation leads to increased sodium current density and neuronal membrane excitability.
• Neuronal hyperexcitability, driven by sodium channel upregulation, is proposed as the basis for epileptic seizures in NHE1 mutant mice.