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Striatal vessels receive phosphorylated tyrosine hydroxylase-rich innervation from midbrain dopaminergic neurons  [PDF]
Domingo Afonso-Oramas,Ignacio Cruz-Muros,Javier Castro-Hernández,Josmar Salas-Hernández,Pedro Barroso-Chinea,Sonia García-Hernández,José L. Lanciego,Tomás González-Hernández
Frontiers in Neuroanatomy , 2014, DOI: 10.3389/fnana.2014.00084
Abstract: Nowadays it is assumed that besides its roles in neuronal processing, dopamine (DA) is also involved in the regulation of cerebral blood flow. However, studies on the hemodynamic actions of DA have been mainly focused on the cerebral cortex, but the possibility that vessels in deeper brain structures receive dopaminergic axons and the origin of these axons have not been investigated. Bearing in mind the evidence of changes in the blood flow of basal ganglia in Parkinson’s disease (PD), and the pivotal role of the dopaminergic mesostriatal pathway in the pathophysiology of this disease, here we studied whether striatal vessels receive inputs from midbrain dopaminergic neurons. The injection of an anterograde neuronal tracer in combination with immunohistochemistry for dopaminergic, vascular and astroglial markers, and dopaminergic lesions, revealed that midbrain dopaminergic axons are in close apposition to striatal vessels and perivascular astrocytes. These axons form dense perivascular plexuses restricted to striatal regions in rats and monkeys. Interestingly, they are intensely immunoreactive for tyrosine hydroxylase (TH) phosphorylated at Ser19 and Ser40 residues. The presence of phosphorylated TH in vessel terminals indicates they are probably the main source of basal TH activity in the striatum, and that after activation of midbrain dopaminergic neurons, DA release onto vessels precedes that onto neurons. Furthermore, the relative weight of this “vascular component” within the mesostriatal pathway suggests that it plays a relevant role in the pathophysiology of PD.
Chronic Levodopa Administration Followed by a Washout Period Increased Number and Induced Phenotypic Changes in Striatal Dopaminergic Cells in MPTP-Monkeys  [PDF]
Carla DiCaudo, Mario Riverol, I?aki-Carril Mundi?ano, Cristina Ordo?ez, María Hernández, Irene Marcilla, Maria-Rosario Luquin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050842
Abstract: In addition to the medium spiny neurons the mammalian striatum contains a small population of GABAergic interneurons that are immunoreactive for tyrosine hydroxylase (TH), which dramatically increases after lesions to the nigrostriatal pathway and striatal delivery of neurotrophic factors. The regulatory effect of levodopa (L-Dopa) on the number and phenotype of these cells is less well understood. Eleven macaques (Macaca fascicularis) were included. Group I (n = 4) received 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and L-Dopa; Group II (n = 4) was treated with MPTP plus vehicle and Group III (n = 3) consist of intact animals (control group). L-Dopa and vehicle were given for 1 year and animals sacrificed 6 months later. Immunohistochemistry against TH was used to identify striatal and nigral dopaminergic cells. Double and triple labeling immunofluorescence was performed to detect the neurochemical characteristics of the striatal TH-ir cells using antibodies against: TH, anti-glutamate decarboxylase (GAD67) anti-calretinin (CR) anti-dopa decarboxylase (DDC) and anti-dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32). The greatest density of TH-ir striatal cells was detected in the striatum of the L-Dopa treated monkeys and particularly in its associative territory. None of the striatal TH-ir cell expressed DARPP-32 indicating they are interneurons. The percentages of TH-ir cells that expressed GAD67 and DDC was approximately 50%. Interestingly, we found that in the L-Dopa group the number of TH/CR expressing cells was significantly reduced. We conclude that chronic L-Dopa administration produced a long-lasting increase in the number of TH-ir cells, even after a washout period of 6 months. L-Dopa also modified the phenotype of these cells with a significant reduction of the TH/CR phenotype in favor of an increased number of TH/GAD cells that do not express CR. We suggest that the increased number of striatal TH-ir cells might be involved in the development of aberrant striatal circuits and the appearance of L-Dopa induced dyskinesias.
Heterogeneity and Diversity of Striatal GABAergic Interneurons  [PDF]
James M. Tepper,Fatuel Tecuapetla,Osvaldo Ibá?ez-Sandoval
Frontiers in Neuroanatomy , 2010, DOI: 10.3389/fnana.2010.00150
Abstract: The canonical view of striatal GABAergic interneurons has evolved over several decades of neuroanatomical/neurochemical and electrophysiological studies. From the anatomical studies, three distinct GABAergic interneuronal subtypes are generally recognized. The best-studied subtype expresses the calcium-binding protein, parvalbumin. The second best known interneuron type expresses a number of neuropeptides and enzymes, including neuropeptide Y, somatostatin, and nitric oxide synthase. The last GABAergic interneuron subtype expresses the calcium binding protein, calretinin. There is no overlap or co-localization of these three different sets of markers. The parvalbumin-immunoreactive GABAergic interneurons have been recorded in vitro and shown to exhibit a fast-spiking phenotype characterized by short duration action potentials with large and rapid spike AHPs. They often fire in a stuttering pattern of high frequency firing interrupted by periods of silence. They are capable of sustained firing rates of over 200 Hz. The NPY/SOM/NOS interneurons have been identified as PLTS cells, exhibiting very high input resistances, low threshold spike and prolonged plateau potentials in response to intracellular depolarization or excitatory synaptic stimulation. Thus far, no recordings from identified CR interneurons have been obtained. Recent advances in technological approaches, most notably the generation of several BAC transgenic mouse strains which express a fluorescent marker, enhanced green fluorescent protein, specifically and selectively only in neurons of a certain genetic makeup (e.g., parvalbumin-, neuropeptide Y-, or tyrosine hydroxylase-expressing neurons etc.) have led to the ability of electrophysiologists to visualize and patch specific neuron types in brain slices with epifluorescence illumination. This has led to a rapid expansion of the number of neurochemically and/or electrophysiologically identified interneuronal cell types in the striatum and elsewhere. This article will review the anatomy, neurochemistry, electrophysiology, synaptic connections, and function of the three “classic” striatal GABAergic interneurons as well as more recent data derived from in vitro recordings from BAC transgenic mice as well as recent in vivo data.
Distribution of GABAergic Interneurons and Dopaminergic Cells in the Functional Territories of the Human Striatum  [PDF]
Javier Bernácer,Lucía Prensa,José Manuel Giménez-Amaya
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030504
Abstract: The afferent projections of the striatum (caudate nucleus and putamen) are segregated in three territories: associative, sensorimotor and limbic. Striatal interneurons are in part responsible for the integration of these different types of information. Among them, GABAergic interneurons are the most abundant, and can be sorted in three populations according to their content in the calcium binding proteins calretinin (CR), parvalbumin (PV) and calbindin (CB). Conversely, striatal dopaminergic cells (whose role as interneurons is still unclear) are scarce. This study aims to analyze the interneuron distribution in the striatal functional territories, as well as their organization regarding to the striosomal compartment.
Functional Properties of Striatal Fast-Spiking Interneurons  [PDF]
Joshua D. Berke
Frontiers in Systems Neuroscience , 2011, DOI: 10.3389/fnsys.2011.00045
Abstract: Striatal fast-spiking interneurons (FSIs) have a major influence over behavioral output, and a deficit in these cells has been observed in dystonia and Tourette syndrome. FSIs receive cortical input, are coupled together by gap junctions, and make perisomatic GABAergic synapses onto many nearby projection neurons. Despite being critical components of striatal microcircuits, until recently little was known about FSI activity in behaving animals. Striatal FSIs are near-continuously active in awake rodents, but even neighboring FSIs show uncorrelated activity most of the time. A coordinated “pulse” of increased FSI firing occurs throughout striatum when rats initiate one chosen action while suppressing a highly trained alternative. This pulse coincides with a drop in globus pallidus population activity, suggesting that pallidostriatal disinhibition may have a important role in timing or coordinating action execution. In addition to changes in firing rate, FSIs show behavior-linked modulation of spike timing. The variability of inter-spike intervals decreases markedly following instruction cues, and FSIs also participate in fast striatal oscillations that are linked to rewarding events and dopaminergic drugs. These studies have revealed novel and unexpected properties of FSIs, that should help inform new models of striatal information processing in both normal and aberrant conditions.
The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration
Janelle Drouin-Ouellet, Claire Gibrat, Mélanie Bousquet, Frédéric Calon, Jasna Kriz, Francesca Cicchetti
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-137
Abstract: Based on the fact that the myeloid differentiation primary response gene (88) (MyD88) is the most common adaptor protein implicated in toll-like receptor (TLR) signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-), following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence.Our results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice.Our results suggest that subacute MPTP-induced dopaminergic degeneration observed in the central nervous system is MyD88-independent, in contrast to our recent observations that this pathway, in the same cohort of animals, is critical in the loss of dopaminergic neurons in the enteric nervous system.Parkinson's disease (PD) is a neurodegenerative disorder for which the mechanisms of neuronal degeneration are currently unclear. However, sustained neuroinflammation has been suggested to contribute to the pathophysiology of several disorders of the central nervous sys
Impact of intravenous immunoglobulin on the dopaminergic system and immune response in the acute MPTP mouse model of Parkinson’s disease  [cached]
St-Amour Isabelle,Bousquet Mélanie,Paré Isabelle,Drouin-Ouellet Janelle
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-234
Abstract: Intravenous immunoglobulin (IVIg) is a blood-derived product, used for the treatment of immunodeficiency and autoimmune diseases. Since a range of immunotherapies have recently been proposed as a therapeutic strategy for Parkinson’s disease (PD), we investigated the effects of an IVIg treatment in a neurotoxin-induced animal model of PD. Mice received four injections of MPTP (15 mg/kg) at 2-hour intervals followed by a 14-day IVIg treatment, which induced key immune-related changes such as increased regulatory T-cell population and decreased CD4+/CD8+ ratio. The MPTP treatment induced significant 80% and 84% decreases of striatal dopamine concentrations (P < 0.01), as well as 33% and 40% reductions in the number of nigral dopaminergic neurons (P < 0.001) in controls and IVIg-treated mice, respectively. Two-way analyses of variance further revealed lower striatal tyrosine hydroxylase protein levels, striatal homovanillic acid concentrations and nigral dopaminergic neurons (P < 0.05) in IVIg-treated animals. Collectively, our results fail to support a neurorestorative effect of IVIg on the nigrostriatal system in the MPTP-treated mice and even suggest a trend toward a detrimental effect of IVIg on the dopaminergic system. These preclinical data underscore the need to proceed with caution before initiating clinical trials of IVIg in PD patients.
Midbrain dopaminergic neurons generate calcium and sodium currents and release dopamine in the striatum of pups  [PDF]
Diana C. Ferrari,Baya J. Mdzomba,Frédéric Libersat,Constance Hammond
Frontiers in Cellular Neuroscience , 2012, DOI: 10.3389/fncel.2012.00007
Abstract: Midbrain dopaminergic neurons (mDA neurons) are essential for the control of diverse motor and cognitive behaviors. However, our understanding of the activity of immature mDA neurons is rudimentary. Rodent mDA neurons migrate and differentiate early in embryonic life and dopaminergic axons enter the striatum and contact striatal neurons a few days before birth, but when these are functional is not known. Here, we recorded Ca2+ transients and Na+ spikes from embryonic (E16–E18) and early postnatal (P0–P7) mDA neurons with dynamic two-photon imaging and patch clamp techniques in slices from tyrosine hydroxylase-GFP mice, and measured evoked dopamine release in the striatum with amperometry. We show that half of identified E16–P0 mDA neurons spontaneously generate non-synaptic, intrinsically driven Ca2+ spikes and Ca2+ plateaus mediated by N- and L-type voltage-gated Ca2+ channels. Starting from E18–P0, half of the mDA neurons also reliably generate overshooting Na+ spikes with an abrupt maturation at birth (P0 = E19). At that stage (E18–P0), dopaminergic terminals release dopamine in a calcium-dependent manner in the striatum in response to local stimulation. This suggests that mouse striatal dopaminergic synapses are functional at birth.
The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities
Tatsunori Maekawa, Sayuri Mori, Yui Sasaki, Takashi Miyajima, Sadahiro Azuma, Etsuro Ohta, Fumiya Obata
Molecular Neurodegeneration , 2012, DOI: 10.1186/1750-1326-7-15
Abstract: The TG mouse expressed I2020T LRRK2 in dopaminergic (DA) neurons of the substantia nigra, ventral tegmental area, and olfactory bulb. In both the beam test and rotarod test, the TG mice exhibited impaired locomotive ability in comparison with their non-transgenic (NTG) littermates. Although there was no obvious loss of DA neurons in either the substantia nigra or striatum, the TG brain showed several neurological abnormalities such as a reduced striatal dopamine content, fragmentation of the Golgi apparatus in DA neurons, and an increased degree of microtubule polymerization. Furthermore, the tyrosine hydroxylase-positive primary neurons derived from the TG mouse showed an increased frequency of apoptosis and had neurites with fewer branches and decreased outgrowth in comparison with those derived from the NTG controls.The I2020T LRRK2 TG mouse exhibited impaired locomotive ability accompanied by several dopaminergic neuron abnormalities. The TG mouse should provide valuable clues to the etiology of PD caused by the LRRK2 mutation.
Simultaneous Identification of Tyrosine Hydroxylase and Choline Acetyltransferase Neurons
A.O. Ihunwo,R. Schliebs
Journal of Animal and Veterinary Advances , 2012,
Abstract: Tyrosine Hydroxylase (TH) and Choline Acetyltransferase (ChAT) immunoreactivity were examined in the adult mouse brain by a modified double labelling immunofluorescence method. Mice were transcardially perfused with saline followed by fixative (4% paraformaldehyde in 0.1M phosphate buffer, pH 7.4). Frozen brain was cut at 30 m thickness for light microscopy. All staining procedures were conducted under room temperature. Dopaminergic neurons were identified from Cy2-coupled-donkey-anti-rabbit antibody and cholinergic neurons by Cy3-coupleddonkey-anti-goat for ChAT. The cell bodies of both TH- and ChAT- positive neurons with their respective axonal and dendritic processes were easily visible. This method proved reliable for simultaneous demonstration, in the same brain tissue sections, of TH- and ChAT-containing neurons.
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