N-methyl-D-aspartate receptors mediate activity-dependent down-regulation of potassium channel genes during the expression of homeostatic intrinsic plasticity

Using whole-cell patch clamp recording and unbiased gene expression profiling in rat dissociated hippocampal neurons cultured at high density, we demonstrate here that chronic activity blockade induced by the sodium channel blocker tetrodotoxin leads to a homeostatic increase in action potential firing and down-regulation of potassium channel genes. In addition, chronic activity blockade reduces total potassium current, as well as protein expression and current of voltage-gated Kv1 and Kv7 potassium channels, which are critical regulators of action potential firing. Importantly, inhibition of N-Methyl-D-Aspartate receptors alone mimics the effects of tetrodotoxin, including the elevation in firing frequency and reduction of potassium channel gene expression and current driven by activity blockade, whereas inhibition of L-type voltage-gated calcium channels has no effect. High-density cultures of dissociated hippocampal neurons (330 neurons/cm2) were treated for 48 hours with vehicle contrl (DMSO), the sodium channel blocker tetrodotoxin (TTX) or the GABA-A receptor antagonist bicuculine, four replicates each