| Description |
The striatum is the key input nucleus of the basal ganglia, which critically mediate normal action selection. Coordinated neuroplasticity within striatonigral and striatopallidal efferent neuron subpopulations of striatum facilitates the maintenance of learned behaviors. In this regard, abnormal striatal plasticity is implicated in compulsive and addictive behaviors. The immediate-early gene, Arc (activity-regulated, cytoskeleton-associated), critically mediates such normal neuroplasticity. In normal animals, more striatonigral than striatopallidal neurons contain cytoplasmic Arc mRNA, despite equivalent transcriptional activation of the Arc gene. Thus, these neuronal populations may differentially regulate Arc mRNA posttranscriptional processing and/or cytoplasmic localization and, consequently, utilize different mechanisms of synaptic plasticity. Therefore, these studies determined the subcellular basis for such differential cytoplasmic localization of Arc in striatal efferent neuron subpopulations. First, we characterized the striatal expression of eIF4A3, which regulates cytoplasmic Arc stability in vitro through the process of translation-dependent mRNA decay. Then, to assess whether phenotypic expression differences are unique to Arc, we investigated a similarly regulated immediate-early gene, zif268/egr-1, which is not subject to cytoplasmic translation-dependent mRNA decay, as well as dendritically localized, but constitutively expressed, Map2. Like Arc, normal animals had more striatonigral than striatopallidal neurons with zif268 mRNA in the peri-nuclear cytoplasm, whereas Map2 expression showed no phenotypic differences. Importantly, striatopallidal neurons had predominately nuclear zif268 retention whereas striatonigral neurons had predominately cytoplasmic zif268 localization. Finally, examining transcriptional activation and cytoplasmic expression of Arc in striatopallidal and striatonigral neurons subsequent to partial dopamine denervation induced by methamphetamine (METH) revealed increased basal Arc expression, but impaired activity-induced transcription of Arc in METH- vs saline-pretreated rats. Furthermore, METH-pretreated rats showed blunted cytoplasmic Arc localization. Interestingly, cytoplasmic localization of zif268 was also disrupted by partial dopamine loss, suggesting that dopamine may contribute to cytoplasmic mRNA localization in striatal efferent neurons. The present findings suggest that striatonigral and striatopallidal neurons differentially regulate posttranscriptional processing and/or nuclear export of activityregulated mRNAs, highlighting a novel, unexplored subcellular difference in striatal efferent neuron subpopulations. These data further suggest that striatal efferent neuron subpopulations may normally utilize different mechanisms of synaptic plasticity to coordinate basal ganglia signaling. |
