A Dopaminergic Axon Lattice in the Striatum and Its Relationship with Cortical and Thalamic Terminals
ABSTRACT Interactions between glutamatergic corticostriatal afferents and dopaminergic nigrostriatal afferents are central to basal ganglia function. The thalamostriatal projection provides a glutamatergic innervation of similar magnitude to the corticostriatal projection. We tested the hypotheses that (1) thalamostriatal synapses have similar spatial relationships with dopaminergic axons as corticostriatal synapses do and (2) the spatial relationships between excitatory synapses and dopaminergic axons are selective associations. We examined at the electron microscopic level rat striatum immunolabeled to reveal vesicular glutamate transporters (VGluTs) 1 and 2, markers of corticostriatal and thalamostriatal terminals, respectively, together with tyrosine hydroxylase (TH) to reveal dopaminergic axons. Over 80% of VGluT-positive synapses were within 1 microm of a TH-positive axon and >40% were within 1 microm of a TH-positive synapse. Of structures postsynaptic to VGluT1- or VGluT2-positive terminals, 21 and 27%, respectively, were apposed by a TH-positive axon and about half of these made synaptic contact. When structures postsynaptic to VGluT-positive terminals and VGluT-positive terminals themselves were normalized for length of plasma membrane, the probability of them being apposed by, or in synaptic contact with, a TH-positive axon was similar to that of randomly selected structures. Extrapolation of the experimental data to more closely reflect the distribution in 3D reveals that all structures in the striatum are within approximately 1 microm of a TH-positive synapse. We conclude that (1) thalamostriatal synapses are in a position to be influenced by released dopamine to a similar degree as corticostriatal synapses are and (2) these associations arise from a nonselective dopaminergic axon lattice.
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ABSTRACT: The spiny dendrites of striatal projection neurons integrate synaptic inputs of different origins to regulate movement. It has long been known that these dendrites lose spines and display atrophic features in Parkinson's disease (PD), but the significance of these morphological changes has remained unknown. Some recent studies reveal a remarkable structural plasticity of striatal spines in parkinsonian rodents treated with L-3,4-dihydroxyphenylalanine (L-DOPA), and they demonstrate an association between this plasticity and the development of dyskinesia. These studies used different approaches and animal models, which possibly explains why they emphasize different plastic changes as being most closely linked to dyskinesia (such as a growth of new spines in neurons of the indirect pathway, or a loss of spines in neurons of the direct pathway, or the appearance of spines with aberrant synaptic features). Clearly, further investigations are required to reconcile these intriguing findings and integrate them in a coherent pathophysiological model. Nevertheless, these studies may mark the beginning of a new era for dyskinesia research. In addition to addressing neurochemical and molecular events that trigger involuntary movements, there is a need to better understand the long-lasting structural reorganization of cells and circuits that maintain the brain in a "dyskinesia-prone" state. This may lead to the identification of new efficacious approaches to prevent the complications of dopaminergic therapies in PD. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.Movement Disorders 03/2015; 30(4). DOI:10.1002/mds.26139 · 5.63 Impact Factor
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ABSTRACT: Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.Brain Structure and Function 03/2015; DOI:10.1007/s00429-015-1029-4 · 4.57 Impact Factor
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ABSTRACT: Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. Copyright © 2015. Published by Elsevier Ltd.Progress in Neurobiology 02/2015; 127-128. DOI:10.1016/j.pneurobio.2015.02.002 · 10.30 Impact Factor