Aberrant Restoration of Spines and their Synapses in L-DOPA-Induced Dyskinesia: Involvement of Corticostriatal but Not Thalamostriatal Synapses

Abstract

We examined the structural plasticity of excitatory synapses from corticostriatal and thalamostriatal pathways and their postsynaptic targets in adult Sprague-Dawley rats to understand how these striatal circuits change in L-DOPA-induced dyskinesias (LIDs). We present here detailed electron and light microscopic analyses that provide new insight into the nature of the structural and synaptic remodeling of medium spiny neurons in response to LIDs. Numerous studies have implicated enhanced glutamate signaling and persistent long-term potentiation as central to the behavioral sensitization phenomenon of LIDs. Moreover, experience-dependent alterations in behavior are thought to involve structural modifications, specifically alterations in patterns of synaptic connectivity. Thus, we hypothesized that in the striatum of rats with LIDs, one of two major glutamatergic pathways would form new or altered contacts, especially onto the spines of medium spiny neuron (MSNs). Our data provide compelling evidence for a dramatic rewiring of the striatum of dyskinetic rats and that this rewiring involves corticostriatal but not thalamostriatal contacts onto MSNs. There is a dramatic increase in corticostriatal contacts onto spines and dendrites that appear to be directly linked to dyskinetic behaviors, since they were not seen in the striatum of animals that did not develop dyskinesia. There is also an aberrant increase in spines receiving more than one excitatory contact(i.e., multisynaptic spines) in the dyskinetic animals compared with the 6-hydroxydopamine-treated and control rats. Such alterations could substantially impair the ability of striatal neurons to gate cortically driven signals and contribute to the loss of bidirectional synaptic plasticity.

Striatal Cholinergic Cell Ablation Attenuates l-DOPA Induced Dyskinesia in Parkinsonian Mice

“…The observation that L-DOPA fully restored the stepping deficit in striatal ChI-depleted parkinsonian mice also argues that the attenuated LID is not due to a decreased response to L-DOPA and further indicates the involvement of different neural circuitries underlying LID and akinesia. In addition to the possible involvement of cholinergic muscarinic receptors in LID (Ding et al, 2011), nicotinic acetylcholine receptor agonists have also been shown to reduce LID in partially DA denervated animals (Bordia et al, 2010;Quik et al, 2013), which is believed to occur through activation of presynaptic nicotinic receptors on DA terminals to promote DA release (Huang et al, 2011;Quik et al, 2013;Zhang et al, 2013; which may not be as significant in our model with near complete denervation), and release of glutamate from afferents from cortex and thalamus (Ding et al, 2008;Parikh et al, 2010). The importance of nondopaminergic transmitter systems that interact with dopaminergic projection in PD is apparent, and therefore pharmacologic agents directed toward serotonin, glutamate, adenosine, and cannabinoids are being investigated for potential anti-parkinsonian and anti-dyskinetic action (for review, see Pisani et al, 2007;Buck and Ferger, 2010;Oldenburg and Ding, 2011;Kalia et al, 2013).…”

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

“…Indeed, long-term changes in gene expression, intracellular signaling pathways, neuronal plasticity, and morphology have all been linked to the expression of LIDs (Santini et al, 2009;Cenci and Konradi, 2010;Feyder et al, 2011;Huot et al, 2011;Rangel-Barajas et al, 2011;Zhang et al, 2013b). Moreover, these changes may occur via numerous neurotransmitter systems, such as the dopaminergic, glutamatergic, serotonergic, and others, which are all implicated in the development and maintenance of LIDs (Carta and Bezard, 2011;Huot et al, 2011;Blandini and Armentero, 2012;Duty, 2012;Rylander, 2012;Huot et al, 2013).…”

Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a Calcium-Binding Protein, Reduces L-DOPA-Induced Dyskinesias in Mice

“…The list of target proteins includes cationic channels (60), membrane receptors (32,61) and membrane docking proteins (33). Since a wide variety of mechanisms underlie synaptic changes associated with LID, including abnormal dendritic spine increases in denervated D2R-containing striatal neurons (38) involved in corticostriatal synapses (62), several additional mechanisms could be related to DREAM-mediated changes in LID based on its presence in the cell body as discussed below.…”