Brain sodium channels (NaChs) are regulated by various neurotransmitters such as acetylcholine, serotonin and dopamine. However, it is not known whether NaCh activity is regulated by glutamate, the principal brain neurotransmitter. We show here that activation of metabotropic glutamate receptor (mGluR) subtype 1 regulates fast transient (INaT) and persistent Na+ currents (INaP) in cortical pyramidal neurons. The selective agonist of group I mGluR (S)-3,5-dihydroxyphenylglycine (DHPG) reduced action potential amplitude and decreased INaT. This reduction was blocked when DHPG was applied in the presence of selective mGluR1 antagonists. The DHPG-induced reduction of the current was accompanied by a shift of both the inactivation curve of INaT and the activation curve of INaP. These effects were dependent on the activation of PKC. The respective role of these two regulatory processes on neuronal excitability was determined by simulating transient and persistent Na+ conductances (GNaT & GNaP) with fast dynamic-clamp techniques. The facilitated activation of GNaP increased excitability near the threshold, but when combined with the down-regulation of GNaT, repetitive firing was strongly decreased. Consistent with this finding, the mGluR1 antagonist LY367385 increased neuronal excitability when glutamatergic synaptic activity was stimulated with high external K+. We conclude that mGluR1-dependent regulation of Na+ current depresses neuronal excitability which thus might constitute a novel mechanism of homeostatic regulation acting during intense glutamatergic synaptic activity.