Region-Specific Knockout of c-Fos in dopamine D1 receptor (D1R)-expressing cells alters evoked activity and D1R-mediated responses in mouse nucleus accumbens (NAc) neurons

San Diego

Congreso; 2004 Society for Neuroscience Meeting; 2004

The immediate early gene (IEG) c-fos encodes a transcription factor that can be rapidly activated by a variety of stimuli including neurotransmitters and addictive drugs. c-Fos proteins in turn regulate expression of other genes encoding receptors, intracellular signaling proteins, and ion channels, thereby modulating neuronal activity. Stimulation of D1Rs increases cAMP/PKA activity and phosphorylation of CREB, an action critical for cocaine-induced c-fos expression in the mesoaccumbens DA system. Here, we have studied mice in which c-fos is primarily mutated in neurons expressing D1Rs. Specifically, whole-cell current clamp recordings were performed in mouse brain slices to determine whether the membrane properties and D1R-mediated responses are altered by knockout of c-fos in medium spiny neurons of the NAc. As compared to neurons recorded from wild-type mice, those recorded from c-fos mutant mice exhibited an increased number of Na+ spikes during membrane depolarization as well as decreased rheobase, and dampened after-hyperpolarization. In addition, whereas the D1R agonist SKF-38393 (1 μM) markedly suppressed evoked spikes in wild-type cells, this suppression was abolished in c-fos mutant D1R-expressing neurons. These findings indicate that genetic deficiency of c-fos increases membrane excitability of NAc neurons while decreasing the efficacy of D1R stimulation. This animal model should be useful for further investigation regarding possible involvement of c-fos in neuronal and behavioral alterations induced by repeated administration of psychostimulants.