Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration

Mao, Limin; Lau, Yuen-Sum; Petroske, Elizabeth; Wang, John Q.

doi:10.1016/s0165-3806(01)00260-7

Cited by 82 publications

(65 citation statements)

References 38 publications

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“…Similar observations have been made with dopamine antagonists and forskolin, with enzyme activity increases being greater and occurring at earlier times and with lower drug doses Young et al, 1998). The exaggerated AAAD response in the partially dopaminedepleted striatum occurs within 24 h after MPTP, at a time when dopamine receptor supersensitivity has not developed (Weihmuller et al, 1990), and there is no serotonergic neuronal sprouting (Rozas et al, 1998) or glia proliferation (Mao et al, 2001). Clozapine-induced tyrosine hydroxylase activation and dopamine metabolism were also amplified in the striatum of the lesioned mice, indicating a heightened response by the remaining dopaminergic neurons.…”

Section: Discussionsupporting

confidence: 58%

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Neff¹,

Wemlinger²,

Duchemin³

et al. 2006

J Pharmacol Exp Ther

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Clozapine is efficacious for treating dopaminergic psychosis in Parkinson's disease and ameliorates L-DOPA-induced motor complications. Based on its pharmacology and reported enhancing effects on dopamine metabolism and tyrosine hydroxylase activity, we investigated whether it could modulate the activity of aromatic L-amino acid decarboxylase (AAAD), the second enzyme for the biosynthesis of catecholamines and indoleamines. A single dose of clozapine increased AAAD activity of striatum in a dose-and time-dependent manner. At 1 h, enhanced enzyme activity was characterized by an increased V max for substrate and cofactor and was accompanied by elevated levels of protein in striatum and mRNA in substantia nigra, ventral tegmental area, locus coeruleus, and raphe nuclei. Acute clozapine increased tyrosine hydroxylase activity in striatum but with differing temporal patterns from AAAD and heightened dopamine metabolism. Interestingly, the response of the dopaminergic markers to clozapine was greater following a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. Chronically administered clozapine increased AAAD activity and protein and dopamine metabolism in striatum without affecting tyrosine hydroxylase. Exogenous L-DOPA decarboxylation was accelerated in the striatum of intact and MPTPlesioned mice following acute clozapine, and the effect was exaggerated in the MPTP mice. To identify receptors involved, antagonists of receptors occupied by clozapine were employed. D4, 5-HT1 A , and 5-HT2 A , in addition to D1, D2, and D3, antagonists, augmented AAAD activity in striatum, whereas 5-HT2 C , 5-HT3, muscarinic, and ␣-1 and ␣-2 adrenergic antagonists were ineffective. For the first time, these studies provide evidence that clozapine modulates AAAD activity in the brain and suggests that dopamine and serotonin receptors are involved.Aromatic L-amino acid decarboxylase (AAAD) is a ubiquitous enzyme essential for the formation of catecholamines, indoleamines, and trace amines (Berry et al., 1996). AAAD is not considered to be the rate-limiting enzyme for catecholamine or indoleamine synthesis; however, it is the rate-limiting step for the synthesis of trace amines and becomes rate-limiting for dopamine formation in Parkinson's disease patients treated with L-DOPA. AAAD is a regulated enzyme, and accumulated evidence suggests that its activity in the rodent brain is tuned by short-and long-term mechanisms that apparently involve enzyme activation and induction.Physiological stimuli (Hadjiconstantinou et al., 1988), neurotransmitter receptors (Rossetti et al., 1989(Rossetti et al., , 1990Zhu et al., 1992;Hadjiconstantinou et al., 1993Hadjiconstantinou et al., , 1995Cho et al., 1997;Fisher et al., 1998) and second messenger systems (Young et al., 1998) participate in the regulation of enzyme activity. In nigrostriatal neurons, dopamine appears to regulate AAAD via D1-and D2-like receptors. Indeed, acute blockade of dopamine D1-like receptors with SCH23390 and of dopamine D2-like receptors with haloperidol, ...

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Section: Discussionsupporting

confidence: 58%

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Neff¹,

Wemlinger²,

Duchemin³

et al. 2006

J Pharmacol Exp Ther

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“…Nonetheless, the consistent finding among all the reports is that actively dividing neuron progenitor cells do present in SN as evidenced by BrdU labeling [20][21][22]. Instead of differentiating into dopaminergic neurons, these cells either remain as uncommitted [23] and give rise to new mature glial cells [24].…”

Section: Discussionsupporting

confidence: 69%

Post-MPTP Treatment with Granulocyte Colony-Stimulating Factor Improves Nigrostriatal Function in the Mouse Model of Parkinson’s Disease

McCollum

Cohen

et al. 2010

Mol Neurobiol

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The neuroprotective effects of granulocyte colony-stimulating factor (G-CSF) were reported in several neurological disease models, including Parkinson's disease (PD). In the present study, we investigated the therapeutic effect of G-CSF after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD was established. G-CSF was subcutaneously administered into C57BL/6 mice that had undergone systemic MPTP injections. We found that G-CSF treatment markedly increased the number of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the G-CSF-treated group. Consistent with this finding, we found a significant increase in dopamine release under high K(+) stimulation in the striatum of the G-CSF-treated animals compared to the MPTP-exposed mice. Finally, we observed a persistent recovery of locomotor function in the G-CSF-treated animals. These results suggest the potential therapeutic value of G-CSF in treating PD. However, our bromodeoxyuridine labeling experiment failed to identify any newly generated dopaminergic neurons in SNpc. This might indicate an indirect effect of G-CSF on cell proliferation. The underlying mechanism of G-CSF is under further investigation.

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“…Striatal TH interneurons (THINs) were first described immunocytochemically in the primate (Dubach et al, 1987) and subsequently in a host of other species, including mice (Mao et al, 2001;Petroske et al, 2001), rats (Meredith et al, 1999;Robinson et al, 2002), and humans (Porritt et al, 2000;Petroske et al, 2001;Cossette et al, 2004Cossette et al, , 2005a. Interest in these neurons intensified after it was reported consistently that the number of striatal THINs increased greatly after 6-hydroxydopamine (6-OHDA) or MPTP lesions that destroyed the nigrostriatal dopamine (DA) innervation.…”

Section: Introductionmentioning

confidence: 99%

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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Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration

Cited by 82 publications

References 38 publications

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Clozapine Modulates Aromatic l-Amino Acid Decarboxylase Activity in Mouse Striatum

Post-MPTP Treatment with Granulocyte Colony-Stimulating Factor Improves Nigrostriatal Function in the Mouse Model of Parkinson’s Disease

Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

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