Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment

Belujon, Pauline; Lodge, Daniel J.; Grace, Anthony A.

doi:10.1002/mds.23245

Cited by 50 publications

(41 citation statements)

References 38 publications

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“…With new calcium-permeable AMPA receptors inserted into the postsynaptic membrane of mushroom spines and their multiple synaptic surfaces in the dyskinetic striatum, LTP could be enhanced (Stein et al, 2003;Yudowski et al, 2013). Thus, excess production of LTP, noted for the dyskinetic striatum (Picconi et al, 2003;Belujon et al, 2010), may result from an increase in excitatory drive at single spines, which have potentially added new calcium-permeable AMPA receptors, and have been associated with the development and maintenance of LIDs (Kobylecki et al, 2010;Yudowski et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…First, the loss of spines and their corticostriatal connections occurs specifically in the indirect pathway neurons following dopamine depletion, which is attributed to elevations in dendritic excitability (Day et al, 2006;Shen et al, 2008;Belujon et al, 2010;Peterson et al, 2012). Indeed, the increase in excitability seems to be caused by the loss of inhibitory signaling at the dopamine D2 receptor .…”

Section: Discussionmentioning

confidence: 99%

“…Following chronic L-DOPA treatment, the striata of dyskinetic ϩ rats lose the ability to establish a form of homeostatic plasticity at glutamatergic synapses, termed "depotentiation," in vitro (Picconi et al, 2003. When MSNs responsible for this loss are examined in vivo, corticostriatal transmission onto indirect pathway neurons becomes abnormally potentiated in both dyskinetic ϩ and dyskinetic Ϫ rats, but LTP at indirect pathway neurons in the dyskinetic ϩ group is characterized as unstable and differs significantly from that in the dyskinetic Ϫ rats (Belujon et al, 2010). Direct pathway neurons, however, retain a form of LTD comparable to that seen in untreated parkinsonian rats (Belujon et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Meredith²,

Mendoza-Elias

et al. 2013

Journal of Neuroscience

111

149

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Zhang

Meredith²,

Mendoza-Elias

et al. 2013

Journal of Neuroscience

111

149

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“…It could have been that MSNs belonging to different response clusters represent different types of cells. In our study design, which involved extracellular recordings from behaving monkeys, we were not able to tag or characterize single cells (Belujon et al, 2010;Flores-Barrera et al, 2010). However, we could examine the spiking parameters of the cells, which are often used to classify cells recorded in the same location into different types (for example, in our study, MSNs vs TANs).…”

Section: Msns Response Profile Does Not Reflect the Neurons' Intrinsimentioning

confidence: 99%

Temporal Convergence of Dynamic Cell Assemblies in the Striato-Pallidal Network

Adler¹,

Katabi²,

Finkes³

et al. 2012

J. Neurosci.

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The basal ganglia (BG) have been hypothesized to implement a reinforcement learning algorithm. However, it is not clear how information is processed along this network, thus enabling it to perform its functional role. Here we present three different encoding schemes of visual cues associated with rewarding, neutral, and aversive outcomes by BG neuronal populations.We studied the response profile and dynamical behavior of two populations of projection neurons [striatal medium spiny neurons (MSNs), and neurons in the external segment of the globus pallidus (GPe)], and one neuromodulator group [striatal tonically active neurons (TANs)] from behaving monkeys. MSNs and GPe neurons displayed sustained average activity to cue presentation. The population average response of MSNs was composed of three distinct response groups that were temporally differentiated and fired in serial episodes along the trial. In the GPe, the average sustained response was composed of two response groups that were primarily differentiated by their immediate change in firing rate direction. However, unlike MSNs, neurons in both GPe response groups displayed prolonged and temporally overlapping persistent activity. The putamen TANs stereotyped response was characterized by a single transient response group. Finally, the MSN and GPe response groups reorganized at the outcome epoch, as different task events were reflected in different response groups.Our results strengthen the functional separation between BG neuromodulators and main axis neurons. Furthermore, they reveal dynamically changing cell assemblies in the striatal network of behaving primates. Finally, they support the functional convergence of the MSN response groups onto GPe cells.

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“…Based on the comparison of the concentration responsecurves of NVP-AAM077 in these conditions 16,17 (Table 1), and the finding that in the dyskinetic state GABA release inhibition appears at higher NVP-AAM077 concentrations (300 nM) than in the parkinsonian state (30 nM), we can conclude that chronic L-DOPA normalizes GluN2A signaling in striato-pallidal neurons and/or the hyperactivity along the indirect pathway. Indeed, L-DOPA inhibits the firing discharge of striato-pallidal neurons in vivo, 29 and, when chronically administered, normalizes zif-268 expression in striato-pallidal neurons 30 and D2-receptor mediated inhibition of striatal neurons. 31 Changes in GLU levels induced by intrastriatal perfusion with GluN2 antagonists are more difficult to interpret, since it is believed that striatal projection neurons are GABAergic in nature and there is no direct GLU projection from the striatum to GP or SNr.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

GluN2A and GluN2B NMDA Receptor Subunits Differentially Modulate Striatal Output Pathways and Contribute to Levodopa-Induced Abnormal Involuntary Movements in Dyskinetic Rats

Mabrouk

Mela

Calcagno

et al. 2013

ACS Chem. Neurosci.

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Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopainduced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it. KEYWORDS: GABA, microdialysis, NMDA receptor subunits, NVP-AAM077, 6-OHDA, Ro 25-6981 A lterations in glutamate (GLU) neurotransmission and, in particular, abnormal function of striatal NMDA receptors, play a key role in driving symptoms of Parkinson's disease (PD) and long-term motor complications (e.g., dyskinesia) associated with L-DOPA therapy.1−3 The focus on the pathogenic role of NMDA receptors (and the therapeutic potential of NMDA receptor antagonists) has further grown after the discovery of their structural and functional heterogeneity. NMDA receptors are heteromers usually containing two NR1 and two NR2 subunits. NR2 subunits, classified into four (A-D) types, 4−6 govern NMDA channel gating and confer different physiopharmacological properties to the receptor-channel complex. 7,8 NMDA receptors containing the GluN2A and GluN2B subunits are highly expressed in the basal ganglia, 9,10 and several studies have reported plastic changes in striatal NR2 subunit expression levels, phosphorylation state and trafficking in response to dopamine (DA) depletion and chronic L-DOPA therapy (reviewed in ref 3).These changes have been pathogenically linked to PD since ifenprodil, the first identified GluN2B selective antagonist, and its analogues such as (R)-(R*,S*)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro 25-6981) attenuated motor impairment in different models of parkinsonism 11−15 By using dual or triple probe microdialysis in awake rats, 16 we have attempted to investigate a possible correlation between the antiparkinsonian/antidyskinetic profiles of GluN2A and GluN2B selective antagonists with their ability to modulate GABA release from globus pallidus (GP) or substantia nigra reticulata (SNr), taken as ...

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Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment

Cited by 50 publications

References 38 publications

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

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

Temporal Convergence of Dynamic Cell Assemblies in the Striato-Pallidal Network

GluN2A and GluN2B NMDA Receptor Subunits Differentially Modulate Striatal Output Pathways and Contribute to Levodopa-Induced Abnormal Involuntary Movements in Dyskinetic Rats

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