L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: Insights into regulation and function

Espadas, Isabel; Darmopil, Sanja; Vergaño-Vera, Eva; Ortiz, Oskar; Oliva, Idaira; Vicario‐Abejón, Carlos; Martı́n, Eduardo D.; Moratalla, Rosario

doi:10.1016/j.nbd.2012.07.012

Cited by 56 publications

(39 citation statements)

References 65 publications

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“…Although we cannot exclude the possibility that DAT is expressed in some striatal TH interneurons in primates but not rodents, it must be noted that the absence of DAT expression is consistent with the resistance of these interneurons (in all species) to destruction by either 6-OHDA or MPTP (Mazloom and Smith, 2006;Tandé et al, 2006;Darmopil et al, 2008). Both 6-OHDA and MPTP enter dopaminergic neurons via the DAT (Gainetdinov et al, 1997;Meredith and Rademacher, 2011;Bové and Perier, 2012;Hare et al, 2013). Thus, the resistance of striatal TH neurons to these neurotoxic compounds is almost certainly attributable to the lack of expression of the DAT and/or VMAT2.…”

Section: Why Are Striatal Thins Not Dopaminergic?mentioning

confidence: 99%

“…In a recent study, Espadas et al (2012) reported that they were able to measure DA of striatal origin evoked by local electrical stimulation with voltammetry after chronic L-DOPA treatment in 6-OHDA-lesioned animals. Although the possibility that striatal gene expression is altered by chronic L-DOPA treatment (Westin et al, 2001;El Atifi-Borel et al, 2009) cannot be excluded, given that a single nigrostriatal axon can occupy up to 5% of the striatal volume (Matsuda et al, 2009), the DA release observed more likely derived from incomplete 6-OHDA lesioning of nigrostriatal axons after intrastriatal injection of 6-OHDA (Espadas et al, 2012).…”

Section: Are Any Neurons In the Striatum Dopaminergic?mentioning

confidence: 99%

“…Although the possibility that striatal gene expression is altered by chronic L-DOPA treatment (Westin et al, 2001;El Atifi-Borel et al, 2009) cannot be excluded, given that a single nigrostriatal axon can occupy up to 5% of the striatal volume (Matsuda et al, 2009), the DA release observed more likely derived from incomplete 6-OHDA lesioning of nigrostriatal axons after intrastriatal injection of 6-OHDA (Espadas et al, 2012).…”

Section: Are Any Neurons In the Striatum Dopaminergic?mentioning

confidence: 99%

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Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

et al. 2015

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Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, L-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

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Section: Why Are Striatal Thins Not Dopaminergic?mentioning

confidence: 99%

Section: Are Any Neurons In the Striatum Dopaminergic?mentioning

confidence: 99%

Section: Are Any Neurons In the Striatum Dopaminergic?mentioning

confidence: 99%

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Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

et al. 2015

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“…To rule out that the different dyskinetic score induced by L-DOPA in DREAM mutant mice is not due to an altered motor response to L-DOPA in these mice, we carried out the cylinder and rotarod tests to measure the antiparkinsonian effect of L-DOPA (42,47). In the cylinder test, naïve mice used both forelimbs similarly, while lesioned mice showed a significant (p<0.001) forelimb use asymmetry ( Figure 4A).…”

Section: The Antiparkinsonian Effect Of L-dopa Is Maintained In Dreammentioning

confidence: 99%

Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a Calcium-Binding Protein, Reduces L-DOPA-Induced Dyskinesias in Mice

Ruiz-DeDiego

Mellström

Vallejo

et al. 2015

Biological Psychiatry

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“…The degeneration of neurons in the SNpc was assessed by counting TH-ir neurons, A-Custained neurons, and TH/A-Cu-Ag doubled-stained neurons unilaterally in every 4th section of the SNpc of all experimental groups (n ¼ 4-6) in which TH immunostaining was performed following the A-Cu-Ag technique (de Olmos et al, 2009). The optical fractionator, Stereoinvestigator program (Microbrightfield Bioscience, Colchester, VT), was used as described (Ares-Santos et al, 2012;Espadas et al, 2012) by an experienced observer unaware of treatment conditions. The outline of the striatum and SNpc (including SN pars lateralis) were drawn at low power ( Â 2) using defined anatomic landmarks (Ares-Santos et al, 2012;Baquet et al, 2009;Granado et al, 2008c), and the number of cells was counted at higher power ( Â 20 for the striatum and Â 100 for the SNpc).…”

Section: Stereological Quantification Of Degenerating Neurons In the mentioning

confidence: 99%

Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining

Ares-Santos

Granado

Espadas

et al. 2013

Neuropsychopharmacol

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131

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Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson's disease (PD) in agreement with animal studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses vs single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or 10 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies was assessed at different time points after methamphetamine by tyrosine hydroxylase immunohistochemistry and silver staining. The 3 Â 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 Â 5 and 1 Â 30. Some degenerating axons could be followed from the striatum to the substantia nigra pars compacta (SNpc). All protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by aminocupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect medium spiny neurons. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days after treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3 days after treatment. Locomotor activity and motor coordination were robustly decreased 1-3 days after treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum.

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L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: Insights into regulation and function

Cited by 56 publications

References 65 publications

Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a Calcium-Binding Protein, Reduces L-DOPA-Induced Dyskinesias in Mice

Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining

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