Abstract
The metabolite of vitamin A, retinoic acid (RA), is known to affect synaptic plasticity in the nervous system and to play an important role in learning and memory. A ubiquitous mechanism by which neuronal plasticity develops in the nervous system is through modulation of voltage-gated Ca2+ (CaV) and voltage-gated K+ channels. However, how retinoids might regulate the activity of these channels has not been determined. Here, we show that RA modulates neuronal firing by inducing spike broadening and complex spiking in a dose-dependent manner in peptidergic and dopaminergic cell types. Using patch-clamp electrophysiology, we show that RA-induced complex spiking is activity dependent and involves enhanced inactivation of delayed rectifier voltage-gated K+ channels. The prolonged depolarizations observed during RA-modulated spiking lead to an increase in Ca2+ influx through CaV channels, though we also show an opposing effect of RA on the same neurons to inhibit Ca2+ influx. At physiological levels of Ca2+, this inhibition is specific to CaV2 (not CaV1) channels. Examining the interaction between the spike-modulating effects of RA and its inhibition of CaV channels, we found that inhibition of CaV2 channels limits the Ca2+ influx resulting from spike modulation. Our data thus provide novel evidence to suggest that retinoid signaling affects both delayed rectifier K+ channels and CaV channels to fine-tune Ca2+ influx through CaV2 channels. As these channels play important roles in synaptic function, we propose that these modulatory effects of retinoids likely contribute to synaptic plasticity in the nervous system.