Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection

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The striatum is thought to play a central role in learning how to choose acts that lead to reward and avoid punishment. Dopamine-dependent modification of striatal synapses in the action selection circuitry has long been thought to be a key step toward this type of learning. The development of new genetic and optical tools has pushed this field forward in the last couple of years, demanding a re-evaluation of models of how experience controls dopamine-dependent synaptic plasticity and how disease states like Parkinson's disease affect the striatal circuitry.

Introduction

The largest of the basal ganglia nuclei, the dorsal striatum integrates information about sensory and motor state conveyed by cortical and thalamic neurons, facilitating the selection of actions that achieve desirable outcomes, like reward, and avoid undesirable ones. Current models of how this happens have been built upon the notion that reward prediction errors signaled by mesencephalic dopaminergic neurons innervating the striatum provide a means by which experience shapes the strength of corticostriatal synapses of principal medium spiny neurons (MSNs) and, in so doing, action selection [1•, 2, 3]. One of the most compelling pieces of evidence for this view comes from the inability of Parkinson's disease patients, who have lost their striatal dopaminergic innervation, to translate thought into action [4].

Although there is strong support for the basic tenets of these models, precisely how dopamine modulates the strength of corticostriatal synapses has been the subject of continuing debate. One of the experimental obstacles that has slowed physiological study is the cellular heterogeneity of the striatum and the seemingly random anatomical distribution of cell types within it. The principal neurons of the striatum are MSNs, constituting roughly 90% of all striatal neurons in most mammals [5]. MSNs can be divided into at least two groups based upon their dopamine receptor expression and axonal projection site: striatopallidal MSNs send their principal axonal arbor to the globus pallidus and express high levels of the D2 dopamine receptor, whereas striatonigral MSNs send their principal axonal arbor to the substantia nigra and express high levels of the D1 dopamine receptor [6]. In physiological studies performed either in vitro or in vivo, these two types of MSNs have been virtually impossible to tell apart, clouding the interpretation of plasticity studies exploring the role of dopamine. The recent development of bacteria artificial chromosome (BAC) transgenic mice in which the expression of D1 or D2 receptors is reported by the expression of red or green fluorescent protein [7] has eliminated this problem and led to a flurry of discoveries about striatal synaptic plasticity  providing the primary motivation for this review.

Section snippets

Long-term depression at glutamatergic synapses on MSNs

Long-term depression (LTD) at MSN glutamatergic synapses is the easiest form of synaptic plasticity to see in the dorsal striatum and, as a consequence, has been studied most thoroughly. Unlike the situation at many other synapses, striatal LTD induction requires pairing of postsynaptic depolarization with moderate to high frequency (not low frequency) afferent stimulation at physiological temperatures [8]. Typically for the induction to be successful, postsynaptic L-type Ca2+ channels and Gq

Long-term potentiation at glutamatergic synapses on MSNs

Less is known about the mechanisms controlling induction and expression of long-term potentiation (LTP) at glutamatergic synapses than LTD. Most of the work describing LTP at glutamatergic synapses has been done with sharp electrodes (either in vivo or in vitro), not with patch clamp electrodes in brain slices that afford greater experimental control and definition of the cellular and molecular determinants of induction. However, there have been a number of studies using these approaches in the

What type of striatal activity normally triggers the induction of synaptic plasticity?

Although most of the induction protocols for synaptic plasticity that have been used to study striatal plasticity are decidedly unphysiological, involving sustained, strong depolarization and/or high frequency synaptic stimulation that induces dendritic depolarization, they do make the necessity of postsynaptic depolarization clear. In a physiological setting, what types of depolarization are likely to gate induction? One possibility is that spikes generated in the axon initial segment (AIS)

Homeostatic plasticity in striatal circuits in Parkinson's disease models

Sorting out how dopamine regulates synaptic plasticity in striatal MSNs has obvious implications for disease states that are triggered by alterations in the function of dopaminergic neurons. Second in prominence among dopamine-dependent disorders only to drug abuse, Parkinson's disease is a common neurodegenerative disorder whose motor symptoms are attributable largely to the loss of dopaminergic neurons innervating the dorsal striatum. In the prevailing model, the excitability of the two major

Concluding remarks

In the last few years, our understanding of the mechanisms controlling synaptic plasticity in the corticostriatal circuits underlying action selection has significantly deepened. Dopamine remains an important player in the induction of plasticity at corticostriatal synapses on principal MSNs, but it is not the only player and its effects are dictated by the type of dopamine receptor expressed. In large measure, this advance has been made possible by the development of BAC transgenic mice that

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

This work was supported by NS34696 to DJS.

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