Trends in Neurosciences
ReviewStriatal microcircuitry and movement disorders
Introduction
The 1980s were a golden era for basal ganglia research, culminating in circuit models that continue to guide hypothesis-based studies of basal ganglia function in clinical and experimental contexts 1, 2, 3, 4. Within the basal ganglia, the striatum is the most prominent nucleus, serving as a major site of input and integration for cortical, thalamic, and midbrain afferents. The striatum is functionally divided along a dorsolateral/ventromedial axis, where the dorsolateral portion subserves sensorimotor functions and the ventromedial portion is more involved in cognitive and limbic functions [5]. Because the focus of this review is neural circuits involved in movement disorders, much of our discussion is concentrated on neural circuits in the dorsolateral striatum.
The projection neurons of the striatum, termed spiny projection neurons (SPNs), integrate glutamatergic inputs from the cortex and thalamus and send GABAergic projections to neurons in downstream basal ganglia nuclei. Based on anatomical projection patterns and biochemical differences, SPNs are divided into two classes. D1-type dopamine receptor-expressing neurons project directly to basal ganglia output nuclei, and are termed ‘direct-pathway’ SPNs (dSPNs), whereas D2-type dopamine receptor-expressing neurons, known as ‘indirect-pathway’ SPNs (iSPNs), project indirectly to basal ganglia output nuclei via the globus pallidus external segment (GPe) and the subthalamic nucleus (STN). These pathways are well segregated in the dorsolateral striatum, and fewer than 5% of SPNs express both classes of dopamine receptors [6]. Activity of dSPNs leads to the disinhibition of motor circuits to facilitate movement. Overactivity of the direct pathway has been proposed to cause hyperkinetic movement disorders such as Huntington's disease (HD), dystonia, and Tourette's syndrome. By contrast, iSPN activity inhibits motor circuits to suppress movement. Overactivity of the indirect pathway is thought to underlie hypokinetic motor symptoms in disorders such as Parkinson's disease (PD).
Approximately 80–90% of striatal SPNs in the dorsolateral striatum fall into the direct/indirect pathway classification system. The remaining 10–20% are found in neurochemically distinct patches throughout the striatum, termed striosomes or patches [4]. SPNs in striosomes typically express D1 receptors and project directly to a subset of dopaminergic neurons in the substantia nigra compacta (SNc). Their direct projections to a subset of dopamine neurons suggest that striosomal SPNs are particularly important for regulating dopamine signaling, but their immediate effects on movement are not clear.
These classic models of basal ganglia function illustrate the importance of understanding how and when specific classes of SPNs are activated. Historically, the cellular and synaptic mechanisms controlling dSPN versus iSPN activation were difficult to elucidate because SPN subtypes could only be differentiated using manually intensive anatomical methods or antidromic stimulation in vivo. This has rapidly changed thanks to the development of transgenic mouse lines that fluorescently label dSPNs, iSPNs, and local interneurons within the striatum 7, 8, 9, 10, 11.
Interneurons tune and regulate the dynamic properties of neural circuits in many brain regions. Interneurons comprise only ∼5% of all striatal neurons, but they are crucial regulators of striatal output. Compared to the broad diversity of interneuron subtypes in the hippocampus [12] and cortex [13], interneurons in the striatum are considerably less heterogeneous (Figure 1). Electrophysiologically, most striatal GABAergic interneurons fall into two categories: (i) fast-spiking interneurons (FSIs) and (ii) persistent and low-threshold spike (PLTSs) interneurons [14]. Neurochemically, FSIs may be distinguished by their expression of the calcium-binding protein parvalbumin (PV), whereas PLTS interneurons express neuropeptides such as somatostatin (SOM), neuropeptide Y (NPY), and the enzyme nitric oxide synthase (NOS). Neurons broadly classified physiologically because PLTSs might also include several subtypes of GABAergic interneurons, including those that express tyrosine hydroxylase (TH) [9]. In addition, about 20% of NPY-expressing interneurons have the electrophysiological properties of neurogliaform cells (NGF) [10]. The striatum also contains calretinin-expressing interneurons, but these cells are much sparser in rodents compared to primates [15] and their electrophysiological properties are not well characterized.
Although this review will focus on inhibitory microcircuits within the striatum, it is important to note the presence of an additional type of interneuron in the striatum that releases the neurotransmitter acetylcholine. Cholinergic interneurons play an important role in regulating striatal output 16, 17, possibly through the modulation of local inhibitory circuits 18, 19.
Section snippets
GABAergic microcircuits in the striatum
FSIs give rise to one of the best-characterized inhibitory microcircuits in the striatum. They are thought to mediate feedforward inhibition because they are activated earlier and at lower thresholds than are SPNs 20, 21. FSIs make strong, dense projections onto SPNs within a 300 μm radius and inhibit SPN firing 8, 21, 22, 23. A single FSI inhibits an estimated total of 135–541 SPNs [24] of both the direct- and indirect-pathway subtypes 8, 23.
NGF cells that express NPY represent a second major
Parkinson's disease
Hypokinetic motor impairments in PD patients are thought to arise from the loss of dopamine neurons in the substantia nigra that densely innervate the striatum. In rate-based models of striatal function, dopamine depletion leads to increased firing rates of iSPNs and excessive activity of neurons in basal ganglia output nuclei 1, 3, 34. In support of these rate-based models, a recent study demonstrated that increased firing of iSPNs was sufficient to decrease movement, and motor impairments in
Huntington's disease
A pathological hallmark of HD is the progressive loss of striatal SPNs. Indirect-pathway SPNs are more susceptible at early stages of the disease, whereas iSPNs, dSPNs, and cortical neurons die at later stages [61]. Animal models of HD have revealed that dysfunction of neural circuits in the striatum and other brain regions can cause motor impairments even without cell death [62].
According to the classic model of basal ganglia function, reduced activity of iSPNs could underlie the hyperkinetic
Dystonia
Dystonia is a clinical disorder in which involuntary and often painful muscle contractions generate twisting and repetitive movements. Although the pathophysiology of dystonia is still poorly understood, symptoms often correlate with increased striatal metabolic activity [76] and reduced GABAergic signaling [77], suggesting dysfunction of inhibitory circuits within the striatum.
A series of experiments characterizing striatal dysfunction in dystonia have been carried out in the dtsz hamster
Tourette syndrome
Tourette syndrome is a movement disorder that first presents during childhood and typically declines in adulthood [89]. Patients with Tourette syndrome exhibit highly stereotyped movements called tics. It has been proposed that the stereotyped motor patterns of tics are driven by some of the same motor circuits as those involved in habit learning [90] and highly repetitive behaviors or compulsions 89, 91.
A circuit-level model of Tourette's syndrome, put forward by Mink and colleagues, posits
Drug-induced motor impairments
Many drugs that alter dopamine signaling can impact movement. Cocaine and amphetamine increase locomotion acutely, and their chronic use can produce repetitive behaviors termed motor stereotypies, which include head bobbing and lip smacking. Psychostimulant-induced hyperlocomotion may arise from increased dopamine levels caused by these drugs, but, owing to the complex and widespread actions of dopamine on most synapses and cell types in the striatum [99], the specific neural circuits involved
Concluding remarks
A growing body of evidence points to dysfunction of striatal microcircuits as a common theme in a variety of movement disorders. Changes in FSIs, for example, are observed in both hypokinetic and hyperkinetic movement disorders. These observations are reconciled by the fact that FSIs target SPNs in a pathway-selective manner that is regulated by plasticity 8, 25. The selective targeting of subsets of principal neurons by interneurons occurs in various neural circuits [107]. Identifying the
Acknowledgments
The authors would like to thank Robyn Javier for assistance with figure design. Work in the Kreitzer laboratory is supported by National Institutes of Health grants R01NS064984 and R01NS078435 (to A.C.K.), K99 NS076524 (to A.H.G.), and the McKnight Endowment for Neuroscience.
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