Striatal dopamine loss in Parkinson's Disease (PD) sets into play a variety of compensatory responses to help counter dopamine depletion. Most of these changes involve surviving dopamine neurons, but there are also changes in striatal medium spiny neurons (MSNs), which are the major target of dopamine axons. Among these changes are decreases in MSN dendritic length and spine density, which may dampen excessive corticostriatal glutamatergic drive onto MSNs that occurs secondary to dopamine loss. An increasing knowledge of dendritic changes in PD suggests strategies for tracking progressive worsening of symptoms and is opening new ideas on novel therapeutic strategies for PD.
"Our finding revealing a preferential concentration of GPR88 in a large proportion of dendritic spines receiving excitatory asymmetrical synaptic contacts (assumed to be glutamatergic inputs) provides an anatomical basis suggesting a tight interplay between GPR88 and corticostriatal neurotransmission, and is consistent with a modulatory role of glutamate inputs on GPR88 expression. In this respect, degeneration of nigrostriatal dopamine neurons can induce secondary disturbances affecting cortical glutamate inputs to striatal MSNs (Deutch, 2006; Neely et al., 2007). For instance, human post-mortem studies and experimental animal models of Parkinson's disease indicate that striatal dopamine depletion produces dystrophic changes in the dendrites, including decreased spine density, of striatopallidal neurons (Ingham et al., 1989, 1993; Stephens et al., 2005; Zaja- Milatovic et al., 2005; Day et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: GPR88, an orphan G protein-coupled receptor, was designated Strg/GPR88 for striatum-specific G protein-coupled receptor (K. Mizushima et al. (2000)Genomics, 69, 314-321). In this study, we focused on striatal GPR88 protein localization using a polyclonal antibody. We established that the distribution of immunoreactivity in rat brain matched that of GPR88 transcripts and provided evidence for its exclusive neuronal expression. GPR88 protein is abundant throughout the striatum of rat and primate, with expression limited to the two subsets of striatal projection medium spiny neurons (MSNs) expressing preprotachykinin-substance P or preproenkephalin mRNAs. Ultrastructural immunolabelling revealed the GPR88 concentration at post-synaptic sites along the somatodendritic compartments of MSNs, with pronounced preference for dendrites and dendritic spines. The GPR88-rich expression, in both striatal output pathways, designates this receptor as a potential therapeutic target for diseases involving dysfunction of the basal ganglia, such as Parkinson's disease. Hence, we investigated changes of GPR88 expression in a model of Parkinson's disease (unilateral 6-hydroxydopamine-lesioned rats) following repeated L-DOPA treatment. In dopamine-depleted striatum, GPR88 expression was differentially regulated, i.e. decreased in striatopallidal and increased in striatonigral MSNs. L-DOPA treatment led to a normalization of GPR88 levels through dopamine D1 and D2 receptor-mediated mechanisms in striatopallidal and striatonigral MSNs, respectively. Moreover, the removal of corticostriatal inputs, by ibotenate infusion, downregulated GPR88 in striatopallidal MSNs. These findings provide the first evidence that GPR88 is confined to striatal MSNs and indicate that L-DOPA-mediated behavioural effects in hemiparkinsonian rats may involve normalization of striatal GPR88 levels probably through dopamine receptor-mediated mechanisms and modulations of corticostriatal pathway activity.
European Journal of Neuroscience 08/2009; 30(3):397-414. DOI:10.1111/j.1460-9568.2009.06842.x · 3.18 Impact Factor
"Loss of spines along dendrites of striatal projection cells has been described in PD (Day et al., 2006; Deutch 2006; Gerfen 2006; Lach et al., 1992; McNeill et al., 1988; Neely et al., 2007; Stephens et al., 2005; Zaja-Milatovic et al., 2005). Whether the elimination of dendritic spines by striatal projection neurons is a plastic or a protective response to dampen excessive cortical drive and to ensure their own survival is currently a matter of debate (Deutch 2006). Levodopa therapy does not appear to reverse the process. "
[Show abstract][Hide abstract] ABSTRACT: The classical model of the cortico-basal ganglia-cortical circuit, with its indirect and direct pathways, was developed to explain the phenomenon of hypokinesia in Parkinson's disease (PD). The model has undergone refinement, but the emphasis on the basal ganglia side of the equation (dopamine deficiency in the dorsal striatum) remains. Here, a revised version of the basic model incorporates key non-dopaminergic connectivities known to become affected in the course of PD and, thus, the cortico-basal ganglia-cortical circuit appears within the context of the larger pathological process. The central roles of the corticostriatal projection, corticosubthalamic projection, and lower brainstem nuclei are emphasized.
[Show abstract][Hide abstract] ABSTRACT: The proximate cause of Parkinson's disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson's disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures composed of ventral mesencephalon, striatum, and cortex of the neonatal rat, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson's disease.
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