Parkinson Disease: Smith Y

Smith Y, Raju D, Nanda B, Pare JF, Galvan A, Wichmann T. · Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, USA. · Brain Res Bull. · Pubmed #18805468 links to  free full text

Abstract: Although we have gained significant knowledge in the anatomy and microcircuitry of the thalamostriatal system over the last decades, the exact function(s) of these complex networks remain(s) poorly understood. It is now clear that the thalamostriatal system is not a unique entity, but consists of multiple neural systems that originate from a wide variety of thalamic nuclei and terminate in functionally segregated striatal territories. The primary source of thalamostriatal projections is the caudal intralaminar nuclear group which, in primates, comprises the centromedian and parafascicular nuclei (CM/Pf). These two nuclei provide massive, functionally organized glutamatergic inputs to the whole striatal complex. There are several anatomical and physiological features that distinguish this system from other thalamostriatal projections. Although all glutamatergic thalamostriatal neurons express vGluT2 and release glutamate as neurotransmitter, CM/Pf neurons target preferentially the dendritic shafts of striatal projection neurons, whereas all other thalamic inputs are almost exclusively confined to the head of dendritic spines. This anatomic arrangement suggests that transmission of input from sources other than CM/Pf to the striatal neurons is likely regulated by dopaminergic afferents in the same manner as cortical inputs, while the CM/Pf axo-dendritic synapses do not display any particular relationships with dopaminergic terminals. A better understanding of the role of these systems in the functional circuitry of the basal ganglia relies on future research of the physiology and pathophysiology of these networks in normal and pathological basal ganglia conditions. Although much remains to be known about the role of these systems, recent electrophysiological studies from awake monkeys have provided convincing evidence that the CM/Pf-striatal system is the entrance for attention-related stimuli to the basal ganglia circuits. However, the processing and transmission of this information likely involves intrinsic GABAergic and cholinergic striatal networks, thereby setting the stage for complex physiological responses of striatal output neurons to CM/Pf activation. Finally, another exciting development that will surely generate significant interest towards the thalamostriatal systems in years to come is the possibility that CM/Pf may be a potential surgical target for movement disorders, most particularly Tourette syndrome and Parkinson's disease. Although the available clinical evidence is encouraging, these procedures remain empirical at this stage because of the limited understanding of the thalamostriatal systems.

Smith Y, Villalba R. · Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia, USA. · Mov Disord. · Pubmed #18781680 No free full text.

Abstract: Degeneration of the nigrostriatal dopaminergic system is the characteristic neuropathological feature of Parkinson's disease and therapy is primarily based on a dopamine replacement strategy. Dopamine has long been recognized to be a key neuromodulator of basal ganglia function, essential for normal motor activity. The recent years have witnessed significant advances in our knowledge of dopamine function in the basal ganglia. Although the striatum remains the main functional target of dopamine, it is now appreciated that there is dopaminergic innervation of the pallidum, subthalamic nucleus, and substantia nigra. A new dopaminergic- thalamic system has also been uncovered, setting the stage for a direct dopamine action on thalamocortical activity. The differential distribution of D1 and D2 receptors on neurons in the direct and indirect striato-pallidal pathways has been re-emphasized, and cholinergic interneurons are recognized as an intermediary mediator of dopamine-mediated communication between the two pathways. The importance and specificity of dopamine in regulating morphological changes in striatal projection neurons provides further evidence for the complex and multifarious mechanisms through which dopamine mediates its functional effects in the basal ganglia. In this review, the role of basal ganglia dopamine and its functional relevance in normal and pathological conditions will be discussed.

Smith Y, Kieval JZ. · Yerkes Regional Primate Research Center and Dept of Neurology, Emory University, Atlanta, GA 30322, USA. · Trends Neurosci. · Pubmed #11052217 No free full text.

Abstract: The dopaminergic nigropallidal and nigrosubthalamic projections control the activity of the globus pallidus and subthalamic nucleus neurons in both normal and pathological conditions. Intrastriatal dopaminergic neurons increase substantially in animal models of Parkinson's disease. They contain GABA, display the ultrastructural features of interneurons and form axo-axonic synapses with putative cortical-like glutamatergic boutons. The local dendritic release of dopamine by neurons in the substantia nigra pars compacta and ventral tegmental also influences basal ganglia functions. Thus, the long-term belief that the effects of dopamine in the basal ganglia were solely mediated through the nigrostriatal system must be changed to take into account extrastriatal dopaminergic projections and intrastriatal dopaminergic neurons.

Smith Y, Charara A, Hanson JE, Paquet M, Levey AI. · Division of Neuroscience, Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30329, USA. · J Anat. · Pubmed #10923987 links to  free full text

Abstract: Glutamate and GABA neurotransmission is mediated through various types of ionotropic and metabotropic receptors. In this review, we summarise some of our recent findings on the subcellular and subsynaptic localisation of GABA(B) and group I metabotropic glutamate receptors in the striatopallidal complex of monkeys. Polyclonal antibodies that specifically recognise GABA(B)R1, mGluR1a and mGluR5 receptor subtypes were used for immunoperoxidase and pre-embedding immunogold techniques at the light and electron microscope levels. Both subtypes of group I mGluRs were expressed postsynaptically in striatal projection neurons and interneurons where they aggregate perisynaptically at asymmetric glutamatergic synapses and symmetric dopaminergic synaptic junctions. Moreover, they are also strongly expressed in the main body of symmetric synapses established by putative intrastriatal GABAergic terminals. In the globus pallidus, both receptor subtypes are found postsynaptically in the core of striatopallidal GABAergic synapses and perisynaptically at subthalamopallidal glutamatergic synapses. Finally, extrasynaptic labelling was commonly seen in the globus pallidus and the striatum. Moderate to intense GABA(B)R1 immunoreactivity was observed in the striatopallidal complex. At the electron microscope level, GABA(B)R1 immunostaining was commonly found in neuronal cell bodies and dendrites. Many striatal dendritic spines also displayed GABA(B)R1 immunoreactivity. Moreover, GABA(B)R1-immunoreactive axons and axon terminals were frequently encountered. In the striatum, GABA(B)R1-immunoreactive boutons resembled terminals of cortical origin, while in the globus pallidus, subthalamic-like terminals were labelled. Pre-embedding immunogold data showed that postsynaptic GABA(B)R1 receptors are concentrated at extrasynaptic sites on dendrites, spines and somata in the striatopallidal complex, perisynaptically at asymmetric synapses and in the main body of symmetric striatopallidal synapses in the GPe and GPi. Consistent with the immunoperoxidase data, immunoparticles were found in the presynaptic grid of asymmetric synapses established by cortical- and subthalamic-like glutamatergic terminals. These findings indicate that both GABA and glutamate metabotropic receptors are located to subserve various modulatory functions of the synaptic transmission in the primate striatopallidal complex. Furthermore, their pattern of localisation raises issues about their roles and mechanisms of activation in normal and pathological conditions. Because of their 'modulatory' functions, these receptors are ideal targets for chronic drug therapies in neurodegenerative diseases such as Parkinson's disease.

Poisik OV, Mannaioni G, Traynelis S, Smith Y, Conn PJ. · Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322, USA. · J Neurosci. · Pubmed #12514208 links to  free full text

Abstract: Group I metabotropic glutamate receptors (mGluRs) 1 and 5 frequently colocalize in the same neurons throughout the CNS. Because both receptors can couple to the same effector systems, the purpose of their cellular coexpression remains unclear. Here, we report that group I mGluR1 and mGluR5 have distinct functional roles in type II neurons of the rat globus pallidus (GP). Type II GP neurons form a large population of GABAergic projection neurons that are characterized by the presence of inwardly rectifying current I(h), low-threshold voltage-activated calcium current I(t), and activity at rest. Although immunocytochemical analysis reveals a high degree of neuronal colocalization of the two group I mGluRs in the GP, activation of mGluR1 only directly depolarizes type II GP neurons. Interestingly, blockade of mGluR5 by a highly selective antagonist, methylphenylethynylpyridine, leads to the potentiation of the mGluR1-mediated depolarization in this neuronal subpopulation. Metabotropic GluR1 desensitizes during repeated activation with the agonist in type II GP neurons, and blocking mGluR5 prevents the desensitization of the mGluR1-mediated depolarization. Elimination of the activity of protein kinase C (PKC) by an application of 1 microm bisendolylmaleimide or 1 microm chelerythrine, both protein kinase C inhibitors, potentiates the mGluR1-mediated response and prevents the desensitization of mGluR1 in type II GP neurons, suggesting that the effect of mGluR5 on mGluR1 signaling may involve PKC. Together, these data illustrate a novel mechanism by which mGluR1 and mGluR5, members of the same family of G-protein-coupled receptors, can interact to modulate neuronal activity in the rat GP.