Rapid nitric oxide-dependent effects of tumor necrosis factor-alpha on suprachiasmatic nuclei neuronal activity.

The effect of tumor necrosis factor-alpha (TNF-alpha) on excitability and synaptic function was analyzed in slice preparations of the suprachiasmatic nuclei (SCN), the major mammalian circadian pacemaker. TNF-alpha caused a rapid increase in the spontaneous firing rate in most SCN neurons examined that was paralleled by an increase of inhibitory postsynaptic currents. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester abolished these effects. No effect of TNF-alpha was found on miniature synaptic currents. The lack of effect on miniature synaptic currents indicates that TNF-alpha primarily affects neuronal membrane properties to cause the changes in spontaneous firing. TNF-alpha, levels of which show circadian variation in the brain and increase during inflammatory conditions and aging, may thus through nitric oxide induction modulate SCN electrical output to affect downstream circadian rhythms.