Convergent evidence for abnormal striatal synaptic plasticity in dystonia

Abstract

Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor "use" may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes linking etiology to pathophysiology of the disease.

Figure 1

Simplified schematic of primary network involving the basal ganglia, including extrinsic neuromodulatory inputs. Solid lines with triangular arrowheads depict excitatory projections. Dashed lines with oval arrowheads depict inhibitory projections. (Abbreviations: Thal_VA/VL – thalamic ventral anterior and ventrolateral nuclei).

Figure 2

Schematic of neuromodulatory receptors in striatum. Excitatory and inhibitory projections as depicted in Figure 1. DARs in red, AChRs in green, and glutamate receptors in grey. (*) denotes pathway-dependent receptor expression, i.e. DARs on MSN spine shafts are primarily D₁Rs on “direct” pathway MSNs and D₂Rs on the “indirect” pathway MSNs and M₁Rs on both “direct” and “indirect” pathway MSNs, but M₄Rs on “direct” pathway MSNs only. Presynaptic processes depicted without specific postsynaptic targets denote incomplete information on these synapses. Omitted for simplicity: GABA receptors as well as myriad intracellular signaling cascades and their downstream effects on ion channel families and receptor expression/trafficking. (Abbreviations: Glu – glutamate; LTS – low-threshold spiking interneuron; NO – nitric oxide). Based in part on figures in (Breakefield et al., 2008; Kreitzer, 2009; Kreitzer and Malenka, 2008; Pisani et al., 2007; Surmeier et al., 2007).

Figure 3

Conceptual framework for two factors in pathophysiology of dystonia. Shaded area corresponds to dystonia, in which various forms involve different relative contributions from the two factors.