Striatal spine plasticity in Parkinson's disease: pathological or not?

Summary

Parkinson's disease (PD) is characterized by a dramatic loss of dopamine that underlies complex structural and functional changes in striatal projection neurons. A key alteration that has been reported in various rodent models and PD patients is a significant reduction in striatal dendritic spine density. Our recent findings indicate that striatal spine loss is also a prominent feature of parkinsonism in MPTP-treated monkeys. In these animals, striatal spine plasticity is tightly linked with the degree of striatal dopamine denervation. It affects predominantly the sensorimotor striatal territory (i.e. the post-commissural putamen) and targets both direct and indirect striatofugal neurons. However, electron microscopic 3D reconstruction studies demonstrate that the remaining spines in the dopamine-denervated striatum of parkinsonian monkeys undergo major morphological and ultrastructural changes characteristic of increased synaptic efficacy. Although both corticostriatal and thalamostriatal glutamatergic afferents display such plastic changes, the ultrastructural features of pre- and post-synaptic elements at these synapses are consistent with a higher strength of corticostriatal synapses over thalamic inputs in both normal and pathological conditions. Thus, striatal projection neurons and their glutamatergic afferents are endowed with a high degree of structural and functional plasticity. In parkinsonism, the striatal dopamine denervation induces major spine loss on medium spiny neurons and generates a significant remodeling of corticostriatal and thalamostriatal glutamatergic synapses, consistent with increased synaptic transmission. Future studies are needed to further characterize the mechanisms underlying striatal spine plasticity, and determine if it represents a pathological feature or compensatory process of PD.

Introduction

The basal ganglia are a group of interconnected subcortical structures involved in the control of motor, cognitive and limbic functions. The striatum is the main entrance of information to the basal ganglia. It receives topographically organized glutamatergic excitatory inputs from the cerebral cortex and the thalamus. Once processed at the striatal level, the information is channeled via GABAergic projections to the external pallidum (GPe) and/or to the output structures of the basal ganglia, the internal pallidum (GPi) and the substantia nigra pars reticulata (SNr) which, in turn, project to the thalamus and brainstem [1, 2]. The flow of information through the basal ganglia is organized into a “direct” (striato-GPi) pathway and “indirect” pathways that involve the GPe and the subthalamic nucleus (STN). The sources of the striatofugal direct and indirect pathways are all GABAergic neurons, that can be segregated into two populations by their peptide content, and by the preferential expression of dopamine receptors. Neurons of the direct pathway contain substance P/dynorphin and express preferentially dopamine D1-receptors, whereas neurons of the indirect pathway contain enkephalin and express preferentially D2-receptors [3]. In Parkinson's disease (PD), the dopaminergic projection from the substantia nigra pars compacta (SNc) to the striatum degenerates. The resulting lack of striatal dopamine increases the activity of ‘indirect’ striatofugal neurons and decreases the striatal output along the ‘direct’ route. Together, these changes are thought to increase the GABAergic basal ganglia outflow to the thalamus [4]. Many aspects of this model have been challenged over the past decades [5, 6]. One of the most substantial shortcomings of this model is the simplistic view by which dopamine mediates its functional effects through the basal ganglia network. The role of striatal dopamine is, indeed, much more complex than mere excitation or inhibition of striatal projection neurons [7]. Dopamine also plays a critical role in mediating long term synaptic plasticity of striatal glutamatergic afferents so that degeneration of the nigrostriatal system in parkinsonism not only directly affects the level of medium spiny neurons (MSN) activation, but also triggers substantial secondary changes of the synaptic morphology and function in the striatum [8, 9, 10, 11].

Findings from our laboratory and others have demonstrated that the nigrostriatal dopaminergic system plays a key role in regulating morphological and functional spine plasticity in the striatum. In this review, we will summarize findings obtained in various animal models and PD patients indicating that spine loss in the striatum is a key morphological event of parkinsonism that, most likely, contributes to functional changes in corticostriatal transmission in parkinsonian condition. We will also highlight morphological differences and regulatory changes induced by dopamine depletion on glutamatergic transmission at axo-spinous synapses established by cortical versus thalamic inputs to the striatum. Finally, we will briefly discuss recent findings showing that the remaining spines in the striatum of MPTP-treated monkeys undergo complex ultrastructural changes consistent with increased synaptic activity, thereby raising doubt as to whether striatal spine loss and ultrastructural remodeling of axo-spinous glutamatergic synapses represent pathological or compensatory features of PD pathophysiology.