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O.065 Ultrastructural plasticity of corticostriatal and thalamostriatal glutamatergic synapses in Parkinson's disease
Oral presentations / Parkinsonism and Related Disorders 15S2 (2009) S1–S28
them mostly with D1 DA receptor sensitization and deregulated homologous desensitization as well as hyperactivity of both canonical and non-canonical DA signaling pathways. I will review these recent findings and demonstrate that decreasing DA receptor-mediated signaling (i) by increasing D1 receptor internalization and (ii) by inhibiting the Ras-Extracellular signalRegulated Kinase 1/2 non-canonical DA signaling casacade, might reduce LID severity. Strategy (i) uses the lentivirus-mediated overexpression of the G protein-coupled receptor kinase 6 that control the desensitization of DA receptors. Strategy (ii) proposes to use statins that, besides being specific inhibitors of the ratelimiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2. Experiments were performed in both the rodent and primate models of LID. Those results strongly suggest that different strategies might represent a treatment option for managing LID in PD. Parallel Session Thalamic changes in Parkinson’s disease 15:00–16:30
December 15 Hall II
O.064 Thalamic changes in Parkinson’s disease G. Halliday. Prince of Wales Medical Research Institute and the University of New South Wales, Randwick, NSW, Australia One of the most marked differences to be identified in Parkinson’s disease is the change in activity of thalamic neurons in the motor circuits. Because dopamine replacement therapies largely alleviate these motor circuit abnormalities, it has been assumed that pathology in the basal ganglia is entirely responsible for the abberent thalamic activity which then permeates the motor circuits. However, there is considerable evidence that pathology within the thalamus itself contributes to the abnormal neural activity characteristic of Parkinson’s disease. In a series of studies examining the degree of degeneration in the thalamus, we have observed selective neuronal degeneration in the intralaminar thalamic nuclei in patients with levodopa-responsive Parkinson’s disease. The nuclei involved are the caudal intralaminar nuclei (the centre-median/parafascicular complex), the paratenial, cucullar and central lateral nuclei. The centre-median/parafascicular complex provides important glutamatergic feedback from the thalamus to the putamen, and is a pathway that is greatly enlarged in primates. There is 30–40% neuronal loss in this region of the thalamus in idiopathic Parkinson’s disease, with non-parvalbumin containing neurons degenerating the most (70% average loss). Our recent work suggests that the preservation of this pathway may contribute to dystonia in Parkinson’s disease. The central lateral and cucullar thalamic nuclei degenerate by 30–50%, while the parataenial nucleus sustains a 55% loss of neurons in association with significant alpha-synuclein deposition which correlates with disease duration. Damage to these regions appears to impact on cognition, awareness and perception. These studies suggest that direct thalamic pathology contributes to the symptoms of Parkinson’s disease. O.065 Ultrastructural plasticity of corticostriatal and thalamostriatal glutamatergic synapses in Parkinson’s disease Y. Smith, R. Villalba, J.-F. Pare, D. Raju. Yerkes National Primate Research Center, Emory University, School of Medicine, Atlanta, GA, USA The striatum is the entrance of information to the basal ganglia circuitry. It receives glutamatergic innervation from the cerebral cortex and thalamus. Both cortical and thalamic terminals contact dendritic spines of striatal projection neurons, except
S17
for thalamic inputs from the caudal intralaminar nuclei, that terminate predominantly on dendritic shafts. Despite evidence for functional plasticity of glutamatergic transmission in the striatum, very little is known about the morphological and neurochemical substrate underlying these effects. In this presentation, I will review evidence from our laboratory and others showing that both cortical and thalamic glutamatergic synapses in the striatum are endowed with a significant degree of structural plasticity, which likely underlies functional changes in these two neural systems in Parkinson’s disease. Striatal dopamine denervation results in as much as 50% loss of dendritic spines on both direct and indirect striatofugal neurons in the sensorimotor striatum of MPTPtreated monkeys. This spine loss is an early feature of parkisonism correlated with the degree of dopamine denervation, but not parkinsonian motor symptoms. The striatum expresses a higher level of vesicular glutamate transporter 1 (vGluT1), a specific marker of corticostriatal terminals, in parkinsonian condition. The remaining spines contacted by cortical or thalamic inputs in the striatum of parkinsonian monkeys undergo ultrastructural remodeling characterized by an increased spine head volume and postsynaptic density area accompanied with an increased volume of pre-synaptic glutamatergic terminals. Thus, dopamine denervation results in major structural structural changes, which likely underlie functional alterations in corticostriatal and thalamostriatal glutamatergic transmission in Parkinson’s disease. O.066 Is the loss of thalamostriatal neurons protective in parkinsonism? S. Kusnoor1 , E.C. Muly2 , J. Morgan3 , A. Deutch4 . 1 Neuroscience, Vanderbilt University Medical Center, Nashville, TN, 2 Psychiatry, Emory University School of Medicine, Atlanta, GA, 3 Developmental Neurobiology, St Judes Children’s Research Hospital, Memphis, 4 Psychiatry, Pharmacology, Neuroscience, Vanderbilt University Medical Center, Nashville, TN, USA The motor symptoms in Parkinson’s Disease (DA) have classically been attributed to loss of nigrostriatal dopamine neurons. However, PD pathology also involves extra-nigral sites, including loss of neurons in the thalamic centromedian-parafascicular (CM-PF) complex. The consequences of CM-PF cell loss are not clear; animal studies involving CM-PF lesions are difficult to interpret because of involvement of several nuclei adjacent to the CM and PF. One approach to circumvent the involvement of adjacent thalamic nuclei is to generate transgenic animals in which the CM or PF, of both, are lost; this requires identification of a protein specific to the CM-PF. The CM-PF neurons express the glycoprotein Cbln1. Cbln1-expressing PF cells innervate the striatum, where they target dendritic spines and shafts of medium spiny neurons (MSNs). Cbln1 is involved in synaptic development and maintenance, and cbln1 knockout (−/−) mice have decreased cerebellar granule cell synapses. Because MSNs suffer a loss of dendritic spines and associated synapses in PD, we examined MSN dendrites in cbln1−/− mice. We found that cbln1−/− mice have an increase in MSN spine density, with no change in dendritic length, and a parallel increase in the number of axospinous synapses. These observations suggest that loss of Cbln1 (or loss of PF cells) may compensate for some of the striatal changes observed in PD. This is consistent with several recent reports indicating the CM-PF DBS reduces motor symptoms and decreases levodopa-induced dyskinesias, and suggest that loss of thalamostriatal neurons in PD may have protective effects.
them mostly with D1 DA receptor sensitization and deregulated homologous desensitization as well as hyperactivity of both canonical and non-canonical DA signaling pathways. I will review these recent findings and demonstrate that decreasing DA receptor-mediated signaling (i) by increasing D1 receptor internalization and (ii) by inhibiting the Ras-Extracellular signalRegulated Kinase 1/2 non-canonical DA signaling casacade, might reduce LID severity. Strategy (i) uses the lentivirus-mediated overexpression of the G protein-coupled receptor kinase 6 that control the desensitization of DA receptors. Strategy (ii) proposes to use statins that, besides being specific inhibitors of the ratelimiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2. Experiments were performed in both the rodent and primate models of LID. Those results strongly suggest that different strategies might represent a treatment option for managing LID in PD. Parallel Session Thalamic changes in Parkinson’s disease 15:00–16:30
December 15 Hall II
O.064 Thalamic changes in Parkinson’s disease G. Halliday. Prince of Wales Medical Research Institute and the University of New South Wales, Randwick, NSW, Australia One of the most marked differences to be identified in Parkinson’s disease is the change in activity of thalamic neurons in the motor circuits. Because dopamine replacement therapies largely alleviate these motor circuit abnormalities, it has been assumed that pathology in the basal ganglia is entirely responsible for the abberent thalamic activity which then permeates the motor circuits. However, there is considerable evidence that pathology within the thalamus itself contributes to the abnormal neural activity characteristic of Parkinson’s disease. In a series of studies examining the degree of degeneration in the thalamus, we have observed selective neuronal degeneration in the intralaminar thalamic nuclei in patients with levodopa-responsive Parkinson’s disease. The nuclei involved are the caudal intralaminar nuclei (the centre-median/parafascicular complex), the paratenial, cucullar and central lateral nuclei. The centre-median/parafascicular complex provides important glutamatergic feedback from the thalamus to the putamen, and is a pathway that is greatly enlarged in primates. There is 30–40% neuronal loss in this region of the thalamus in idiopathic Parkinson’s disease, with non-parvalbumin containing neurons degenerating the most (70% average loss). Our recent work suggests that the preservation of this pathway may contribute to dystonia in Parkinson’s disease. The central lateral and cucullar thalamic nuclei degenerate by 30–50%, while the parataenial nucleus sustains a 55% loss of neurons in association with significant alpha-synuclein deposition which correlates with disease duration. Damage to these regions appears to impact on cognition, awareness and perception. These studies suggest that direct thalamic pathology contributes to the symptoms of Parkinson’s disease. O.065 Ultrastructural plasticity of corticostriatal and thalamostriatal glutamatergic synapses in Parkinson’s disease Y. Smith, R. Villalba, J.-F. Pare, D. Raju. Yerkes National Primate Research Center, Emory University, School of Medicine, Atlanta, GA, USA The striatum is the entrance of information to the basal ganglia circuitry. It receives glutamatergic innervation from the cerebral cortex and thalamus. Both cortical and thalamic terminals contact dendritic spines of striatal projection neurons, except
S17
for thalamic inputs from the caudal intralaminar nuclei, that terminate predominantly on dendritic shafts. Despite evidence for functional plasticity of glutamatergic transmission in the striatum, very little is known about the morphological and neurochemical substrate underlying these effects. In this presentation, I will review evidence from our laboratory and others showing that both cortical and thalamic glutamatergic synapses in the striatum are endowed with a significant degree of structural plasticity, which likely underlies functional changes in these two neural systems in Parkinson’s disease. Striatal dopamine denervation results in as much as 50% loss of dendritic spines on both direct and indirect striatofugal neurons in the sensorimotor striatum of MPTPtreated monkeys. This spine loss is an early feature of parkisonism correlated with the degree of dopamine denervation, but not parkinsonian motor symptoms. The striatum expresses a higher level of vesicular glutamate transporter 1 (vGluT1), a specific marker of corticostriatal terminals, in parkinsonian condition. The remaining spines contacted by cortical or thalamic inputs in the striatum of parkinsonian monkeys undergo ultrastructural remodeling characterized by an increased spine head volume and postsynaptic density area accompanied with an increased volume of pre-synaptic glutamatergic terminals. Thus, dopamine denervation results in major structural structural changes, which likely underlie functional alterations in corticostriatal and thalamostriatal glutamatergic transmission in Parkinson’s disease. O.066 Is the loss of thalamostriatal neurons protective in parkinsonism? S. Kusnoor1 , E.C. Muly2 , J. Morgan3 , A. Deutch4 . 1 Neuroscience, Vanderbilt University Medical Center, Nashville, TN, 2 Psychiatry, Emory University School of Medicine, Atlanta, GA, 3 Developmental Neurobiology, St Judes Children’s Research Hospital, Memphis, 4 Psychiatry, Pharmacology, Neuroscience, Vanderbilt University Medical Center, Nashville, TN, USA The motor symptoms in Parkinson’s Disease (DA) have classically been attributed to loss of nigrostriatal dopamine neurons. However, PD pathology also involves extra-nigral sites, including loss of neurons in the thalamic centromedian-parafascicular (CM-PF) complex. The consequences of CM-PF cell loss are not clear; animal studies involving CM-PF lesions are difficult to interpret because of involvement of several nuclei adjacent to the CM and PF. One approach to circumvent the involvement of adjacent thalamic nuclei is to generate transgenic animals in which the CM or PF, of both, are lost; this requires identification of a protein specific to the CM-PF. The CM-PF neurons express the glycoprotein Cbln1. Cbln1-expressing PF cells innervate the striatum, where they target dendritic spines and shafts of medium spiny neurons (MSNs). Cbln1 is involved in synaptic development and maintenance, and cbln1 knockout (−/−) mice have decreased cerebellar granule cell synapses. Because MSNs suffer a loss of dendritic spines and associated synapses in PD, we examined MSN dendrites in cbln1−/− mice. We found that cbln1−/− mice have an increase in MSN spine density, with no change in dendritic length, and a parallel increase in the number of axospinous synapses. These observations suggest that loss of Cbln1 (or loss of PF cells) may compensate for some of the striatal changes observed in PD. This is consistent with several recent reports indicating the CM-PF DBS reduces motor symptoms and decreases levodopa-induced dyskinesias, and suggest that loss of thalamostriatal neurons in PD may have protective effects.