Loss and remodeling of striatal dendritic spines in Parkinson's disease: from homeostasis to maladaptive plasticity?

Abstract

In Parkinson's disease (PD) patients and animal models of PD, the progressive degeneration of the nigrostriatal dopamine (DA) projection leads to two major changes in the morphology of striatal projection neurons (SPNs), i.e., a profound loss of dendritic spines and the remodeling of axospinous glutamatergic synapses. Striatal spine loss is an early event tightly associated with the extent of striatal DA denervation, but not the severity of parkinsonian motor symptoms, suggesting that striatal spine pruning might be a form of homeostatic plasticity that compensates for the loss of striatal DA innervation and the resulting dysregulation of corticostriatal glutamatergic transmission. On the other hand, the remodeling of axospinous corticostriatal and thalamostriatal glutamatergic synapses might represent a form of late maladaptive plasticity that underlies changes in the strength and plastic properties of these afferents and the resulting increased firing and bursting activity of striatal SPNs in the parkinsonian state. There is also evidence that these abnormal synaptic connections might contribute to the pathophysiology of L-DOPA-induced dyskinesia. Despite the significant advances made in this field over the last thirty years, many controversial issues remain about the striatal SPN subtypes affected, the role of spine changes in the altered activity of SPNs in the parkinsonisn state, and the importance of striatal spine plasticity in the pathophysiology of L-DOPA-induced dyskinesia. In this review, we will examine the current state of knowledge of these issues, discuss the limitations of the animal models used to address some of these questions, and assess the relevance of data from animal models to the human-diseased condition.

Keywords: Corticostriatal; Dopamine; Glutamate; Monkey; Striatum; Thalamostriatal.

Fig. 1. Light microscopy pictures of a spiny projection neuron (SPN) (a) and an interneuron (b) in dorsal striatum of the non-human primate

a: Golgi-impregnated striatal SPN. These neurons have ovoid or polygonal cell bodies with a maximum diameter of ≤ 25 μm, and extensive dendritic trees. The somata of the neurons are smooth while the dendrites, except for their most proximal portions, are covered with spines. b: Example of an aspiny striatal cholinergic interneuron. This neuron has been immunostained using specific antibodies against the enzyme choline acetyltransferase (ChAT), a specific marker for cholinergic neurons. These neurons have large cell bodies, with a diameter-size between 30–50 μm, and different morphologies (ovoid, elongated or triangular). The length and ramification of their immunostained dendritic trees vary, and usually branch close to the cell body. Scale bar in a and b: 25 μm.

Fig. 2. Tyrosine hydroxylase (TH) immunoreactivity (a) and dendritic spine density in the striatum of partially dopamine depleted MPTP-treated monkeys (b–f)

a: Pseudo-colored image (NIH ImageJ program) of a TH-immunostained section from the monkey commissural striatum. The numbers (1–4) in the caudate (black numbers) and putamen (white numbers) indicate the areas from where the Golgi-impregnated neurons were selected for the dendritic spine analysis showed in e and f. The lowest (complete DA loss) and highest (no DA loss) levels of TH-immunostaining correspond to the numbers 1 and 4, respectively. b–d: Golgi impregnated dendrites (20–30 μm from the soma) from monkey striatal SPNs in control (no DA depletion; 10–12 spines per μm) (b), partial DA depletion (c), and complete DA depletion (4–6 spines per μm) (d). e, f: Histograms showing the dendritic spine density of Golgi-impregnated neurons from commissural striatal areas with different degrees of dopamine depletion. The values in the bars represent the mean of the spine density (mean±SEM) per 10 μm of dendritic length (primary dendrite) from neurons (10 neurons per area) from the corresponding striatal areas indicated by number (1 to 4) and color (black or white) in a. The Abbreviations: Ac: anterior commissure; CD: caudate; IC: internal capsule; Pu: putamen; GPe: Globus pallidus external segment. Scale bars in a: 1 mm, and in b (applies to c and d): 1 μm.

Fig. 3. Glutamatergic terminals and SPNs dendritic spines in the striatum of control and MPTP-treated monkeys

a, b: Electron micrographs of dendritic spines and their corresponding glutamatergic synapses in the striatum of control (a), and MPTP-treated parkinsonian (b) monkeys. a.1, a.2, b.1, b.2: Three-dimensional reconstructions of vGluT1-positive terminals forming axo-spinous synapses in the striatum of control (a.1; a.2) and MPTP-treated parkinsonian (b.1; b.2) monkeys. c: Histograms comparing the quantitative analysis of morphometric parameters (spine head volume, postsynaptic density area, terminal volume) of 3D-reconstructed axo-spine corticostriatal (vGluT1, c) and thalamostriatal (vGluT2, d) synapses in the striatum of control and parkinsonian (c, d) monkeys. In MPTP-treated parkinsonian monkeys (N=3), the spine volume (Vol Spi, μm³), the areas of the postsynaptic densities (PSDs, μm²) and the volume of the presynaptic terminals (μm³) at corticostriatal (c) and thalamostriatal (d) synapses are significantly increased (*, t-test, P<0.001; SigmaPlot) in MPTP-treated monkeys compared with controls (N=3). Scale bar in a (applies to b): 1μm.

Fig. 4. Perisynaptic astrocytes in striatal axo-spine glutamatergic synapses of control and MPTP-treated monkeys

a, b: Examples of single electron micrographs (EM) images of perisynaptic astrocytic processes (Ast) in control (a) and MPTP-treated monkey (b). Glial processes have been pseudocolored in blue (a, b). a.1, a.2, b.1, b.2: Three–dimensional reconstruction of axo-spine synapses formed by a vGluT1-positive terminal (T) and a dendritic spine (Sp) in the striatum of control (a.1, a.2) and MPTP-treated parkinsonian (b.1, b.2) monkey. While axo-spinous interfaces in control (a, a.1, a.2) are only partially surrounded by astroglial processes (Ast), those synapses are almost completely wrapped by enlarged astrocyte (Ast) processes in MPTP-animals (b, b.1, b.2). c, d: Quantitative analysis of the perisynaptic glia in striatal glutamatergic axo-spine synapses. c: Comparison of the surface area (mean±SEM) of perisynaptic glia associated with axo-spine synapses formed vGluT1- and vGluT2-immunopositive terminals in control and MPTP-treated monkeys. The surface of the perisynaptic glia is significantly larger (*, t-test; SigmaPlot) in MPTP-parkinsonian monkeys than in control (p=0.017 for vGluT1, and p=0.06 for vGluT2). d: Comparison of the volume of the perisynaptic glia over the total volume of the spine and the vGluT1- or vGluT2-immunoreactive terminal. This ratio is significantly increased in axo-spines synapses from MPTP-treated animals compared with control (*, t-test, p=0.049 for vGluT1 and p=0.028 for vGluT2, SigmaPlot). No significant difference is found between the volume of perisynaptic glia in axo-spine synapses formed for vGluT1- or vGluT2-positive terminals. Number of animals=3 controls and 3 MPTP-treated monkeys. Total number of reconstructed spines=32 (8 per group). Scale bar in a (applies to b): 1μm.