Signaling in Striatal Neurons: The Phosphoproteins of Reward, Addiction, and Dyskinesia

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The striatum is a deep region of the forebrain involved in action selection, control of movement, and motivation. It receives a convergent excitatory glutamate input from the cerebral cortex and the thalamus, controlled by dopamine (DA) released in response to unexpected rewards and other salient stimuli. Striatal function and its dysfunction in drug addiction or Parkinson's disease depend on the interplay between these neurotransmitters. Signaling cascades in striatal medium-sized spiny neurons (MSNs) involve multiple kinases, phosphatases, and phosphoproteins, some of which are highly enriched in these neurons. They control the properties of ion channels and the plasticity of MSNs, in part through their effects on gene transcription. This chapter summarizes signaling in MSNs and focuses on the regulation of multiple protein phosphatases through DA and glutamate receptors and the role of ERK. It is hypothesized that these pathways are particularly adapted to the specific computing properties of MSNs and the function of the basal ganglia circuits in which they participate.

Introduction

Reward and punishment are two major incentives for learning. Highly sophisticated mechanisms underlying these basic behavioral regulations have been selected during evolution, allowing adaptation and survival of individuals in fairly unpredictable environments. These two powerful mechanisms teach the brain to avoid repeating potentially harmful situations or behaviors, and to look for or repeat those that are potentially beneficial. Arguably, these two deeply engrained mechanisms control to various degrees all types of learning and memory. In mammals, they depend to a large extent on deep brain regions, which regulate cortical functions and control behavior. Over the past decades, progress in understanding the underlying neural circuits and their molecular and cellular bases has been considerable. This progress sheds light on neurological and psychiatric disorders whose pathophysiology and symptoms depend in part on alterations in these learning mechanisms. This chapter is devoted to some of the phosphorylation reactions that are important for reward-controlled or incentive learning, and its pathology, mostly addiction. Importantly, similar brain circuits are involved in the control of movements and their alterations are important in the course of Parkinson's disease (PD).

Reward-controlled learning has been extensively studied from a behavioral standpoint since the pioneering work of Pavlov, Thorndike, and others at the beginning of the twentieth century. The existence of brain reward circuits was then demonstrated by the intracranial self-stimulation experiments of Olds and Milner in the 1950s, and the role of dopamine (DA) in these circuits was rapidly suspected. However, it is only recently that the neural mechanisms underlying these complex processes have been clarified by the work of many laboratories (see Refs. 1, 2, 3, 4 for reviews). DA neurons in the substantia nigra and the ventral tegmental area (VTA) are proposed to code for errors in reward prediction3: they fire in response to unexpected rewards, or, following associative learning, in response to the conditioned stimulus that predicts the reward but not to the primary reward. Conversely, the absence of an expected reward inhibits their firing. Thus, the release of DA appears to be a signal for controlling learning in relation to reward-related events. Recent work shows that some DA neurons also fire for nonrewarding stimuli which nevertheless have motivational salience.5 Schematically, current hypotheses imply that DA released in response to unexpected rewards (or reward-conditioned stimuli) facilitates synaptic plasticity in forebrain circuits and, thus, reinforces associations between specific environmental context and/or cues and a particular behavior. Much experimental and theoretical work has been devoted to the elucidation of the role of DA, with implications for animal and human behavior and pathology, and even “neuroeconomics.” One of the major targets of DA is the striatum, which is described below in more details. Its dorsal region is involved in the control of movements, and DA was first characterized because of the dramatic consequences of its absence in the dorsal striatum, which is responsible for PD.

The study of DA function has progressed in parallel with that of the biological bases of drug addiction. Most, if not all, addictive drugs share the ability to increase extracellular DA in the ventral striatum (nucleus accumbens, NAc), a region of the basal ganglia important for goal-directed behaviors and motivation.1 Addiction is thought to involve a chemically induced abnormal learning process due to the ability of drugs of abuse to directly enhance DA transmission.6, 7 Thus, drugs of abuse divert the mechanisms of reward-controlled learning, progressively driving the behavior toward a compulsive urge for drug intake. It should be kept in mind that “real” addiction results from repeated exposure to drugs in a vulnerable background, in humans as well as in rodents.8 It is remarkable that similar mechanisms of DA-controlled neuronal plasticity take place in the dorsal striatum and are involved in learning motor patterns.9 Recent work suggests a progressive ventro-dorsal shift of the striatal regions critically involved in the action of drugs responsible for the formation of drug-related habits, which is central to addiction.10 In a different context, imbalance of DA control of plasticity in these motor circuits is a key factor in the occurrence of abnormal movements such as dyskinesia in l-DOPA-treated patients with PD. Thus, understanding the mechanisms of action of DA on striatal neurons is important for various aspects of physiology and pathology.

Section snippets

Overview of the Anatomo-Functional Organization of the Striatum and Basal Ganglia

The striatum, which consists of a dorsal region, the caudate–putamen (CP), and a ventral region, the NAc, is the major entry station of the basal ganglia. It is comprised of medium-sized spiny neurons (MSNs) which are GABAergic efferent neurons making up to 95% of striatal neurons in rodents, and of several types of interneurons, including large cholinergic and diverse medium-size GABAergic neurons.11 MSNs receive massive glutamatergic inputs from virtually all cortical areas and the thalamus,

DA Receptors in the Striatum

Paul Greengard and his collaborators showed that cascades of biochemical reactions similar to those identified in the control of liver and muscle glycogen metabolism were critical in the action of neurotransmitters in the nervous system.33, 34 They identified the first DA receptor by its positive coupling to adenylyl cyclase35 and the downstream protein phosphorylation.36 Later, a second type of DA receptor, D2, which is negatively coupled to adenylyl cyclase, was identified, first in the

Glutamate Receptors

Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. It is responsible for the fast excitatory transmission mediated by binding of glutamate to extracellular regions of ligand-gated ion channels, the so-called ionotropic glutamate receptors (iGluR). Glutamate also acts on GPCRs, the metabotropic glutamate receptors (mGluR) that have important modulatory roles. The iGluR comprise two major groups in the context of this discussion, termed after their

Synaptic Plasticity

Synaptic plasticity corresponds to changes in synaptic efficiency (i.e., increased or decreased postsynaptic response for a constant stimulation of the presynaptic element) of various durations. Long-term plasticity (several hours, days, or longer) is thought to be particularly important for learning and memory. The work of many laboratories has allowed the dissection of mechanisms of long-term potentiation (LTP) and long-term depression (LTD), including in the striatum.25, 61, 62 These

The cAMP Cascade

The action of DA on cAMP-production-coupled D1R was one of the first neurotransmitters effects to be identified in the brain and has been extensively studied (Fig. 2). cAMP major action is to bind to the regulatory subunit (R) of cAMP-dependent protein kinase (PKA), a heterotetramer containing two R and two catalytic subunits (C).66 This binding releases the C subunits, which are fully active, phosphorylate membrane-bound and cytosolic substrates, and can penetrate the nucleus to phosphorylate

DARPP-32: A Signaling Hub Important in MSNs

DARPP-32 is a small unstructured protein of about 202 amino acids (its length varies among species).76 Its N-terminal region has sequence identities with protein phosphatase 1 (PP1 also termed phosphoprotein phosphatase 1 PPP1) inhibitors 1A and 1C (see Ref. 77 for a recent review). These three proteins form a family of cAMP/PKA-regulated PP1 inhibitors (PPP1-regulatory subunits 1A–C, or PPP1R1A/B/C, respectively). The motifs involved in interaction with PP1 catalytic subunit (PP1c) comprise a

The Function of Other PKA Substrates Enriched in Striatal Neurons

ARPP-21 and ARPP-16 were described 25 years ago and, although they were clearly regulated by DA and other neurotransmitters,123, 124, 125 their function remained unknown until recently.126 ARPP-21, when phosphorylated by PKA, binds to calmodulin in the presence of Ca2 + and thus inhibits CaM-dependent enzymes.127 Therefore, ARPP-21 has been renamed “regulator of calmodulin signaling” (RCS). RCS is involved in the regulation of PKA substrates that are dephosphorylated by calcineurin and amplifies

The ERK Cascade

Mitogen-activated protein kinases (MAP kinases) are regulated by two upstream kinases, a MAP-kinase-kinase and a MAP-kinase-kinase-kinase, which form a highly conserved 3-kinase signaling modules. One type of MAP kinases, namely, the extracellular signal-regulated kinases 1/2 (ERK1/2), has been shown to play an important role in striatal signaling.130 ERKs are ubiquitous enzymes activated by many extracellular signals including growth factors and neurotransmitters and regulate a variety of

Protein Phosphorylation and Signaling in l-DOPA-Induced Dyskinesia in PD

PD is due to the progressive death of DA neurons in the substantia nigra, resulting in a loss of DA in the dorsal striatum. The lack of basal levels of DA impairs signaling by D2R in striatopallidal neurons and contributes to an imbalance between the indirect and the direct pathway.161 The predominance of the indirect pathway results in a general inhibition of movement initiation (akinesia) and rigidity. The most common treatment of PD is l-DOPA, the metabolic precursor of DA, which alleviates

Functional Considerations and Conclusions

Signaling mechanisms involved in the action of DA and other neurotransmitters in striatal neurons are among the most extensively studied in neurons. Although they share many similarities with other neurons, MSNs are endowed with a set of specific signaling proteins, which are much less abundant or absent in most other cell types (e.g., Gαolf, Gγ7, AC5, PDE10A, DARPP-32, RCS, ARPP-16, etc.). These proteins are likely to provide specific signaling properties suited for the particular

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