Abstract
Striatal medium-sized spiny neurons (MSNs) receive massive glutamate inputs from the cerebral cortex and thalamus and are a major target of dopamine projections. Interaction between glutamate and dopamine signaling is crucial for the control of movement and reward-driven learning, and its alterations are implicated in several neuropsychiatric disorders including Parkinson’s disease and drug addiction. Long-lasting forms of synaptic plasticity are thought to depend on transcription of gene products that alter the structure and/or function of neurons. Although multiple signal transduction pathways regulate transcription, little is known about signal transmission between the cytoplasm and the nucleus of striatal neurons and its regulation. Here we review the current knowledge of the signaling cascades that target the nucleus of MSNs, most of which are activated by cAMP and/or Ca2+. We outline the mechanisms by which signals originating at the plasma membrane and amplified in the cytoplasm are relayed to the nucleus, through the regulation of several protein kinases and phosphatases and transport through the nuclear pore. We also summarize the identified mechanisms of transcription regulation and chromatin remodeling in MSNs that appear to be important for behavioral adaptations, and discuss their relationships with epigenetic regulation.
Highlights
This study demonstrated that psychostimulant drugs (d-amphetamine and cocaine) and morphine, which act by different mechanisms but share the ability to increase extracellular dopamine in the striatum, as well as incentive learning, increased the nuclear concentration of DARPP-32
As a general principle the prevention of “background noise” kinase activity in the nucleus of unstimulated neurons is likely to be important to avoid meaningless nuclear responses. This is probably achieved through the regulated cytoplasmic sequestration of protein kinase (PKA), extracellular signal-regulated kinase (ERK), and other signaling molecules including some transcription factors, as well as by potent phosphatase activities in the nucleus
Identified targets include transcription factors and chromatin components such as histones that modulate the rate of transcription
Summary
Cytonuclear signaling in striatal neurons long range interactions, which are only starting to be deciphered in non-neuronal cells (Fraser and Bickmore, 2007). Besides the PKA and ERK pathways, other signaling cascades are likely to be involved in the regulation of nuclear functions but have received comparatively less attention so far in striatal neurons They include the Ca2+/calmodulin-activated protein kinases (CaMKs) which play a key role in the regulation of gene expression in other neuronal types (Deisseroth and Tsien, 2002; Cohen and Greenberg, 2008). Nuclear traffic provides a means of temporal and spatial control of signaling cascades and is tightly regulated by numerous mechanisms and at multiple levels (see Kaffman and O’Shea, 1999; Poon and Jans, 2005; Terry et al, 2007, for reviews) Because it is central for understanding cytonuclear signaling, we briefly overview the basic principles of nuclear import and export mechanisms, this knowledge has been acquired in other cell types and little is known about the possible specificities of striatal neurons in this matter. We will examine how such regulations apply to signaling proteins important in the striatum, using mostly information obtained in other cell types since very few studies have addressed directly these issues in MSNs
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