Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection

Hirofumi Tokuoka, Shin Ichi Muramatsu, Chiho Sumi-Ichinose, Hiroaki Sakane, Masayo Kojima, Yoshinori Aso, Takahide Nomura, Daniel Metzger, Hiroshi Ichinose

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The tyrosine hydroxylase (TH; EC 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. Here, to further explore the regulatory mechanism of dopamine levels by TH in adult mouse brains, we employed a genetic method to inactivate the Th gene in the nigrostriatal projection using the Cre-loxP system. Stereotaxic injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the substantia nigra pars compacta (SNc), where dopaminergic cell bodies locate, specifically inactivated the Th gene. Whereas the number of TH-expressing cells decreased to less than 40% in the SNc 2 weeks after the AAV-Cre injection, the striatal TH protein level decreased to 75%, 50%, and 39% at 2, 4, and 8 weeks, respectively, after the injection. Thus, unexpectedly, the reduction of TH protein in the striatum, where SNc dopaminergic axons innervate densely, was slower than in the SNc. Moreover, despite the essential requirement of TH for dopamine synthesis, the striatal dopamine contents were only moderately decreased, to 70% even 8 weeks after AAV-Cre injection. Concurrently, in vivo synthesis activity of L-dihydroxyphenylalanine, the dopamine precursor, per TH protein level was augmented, suggesting up-regulation of dopamine synthesis activity in the intact nigrostriatal axons. Collectively, our conditional Th gene targeting method demonstrates two regulatory mechanisms of TH in axon terminals for dopamine homeostasis in vivo: local regulation of TH protein amount independent of soma and trans-axonal regulation of apparent L-dihydroxyphenylalanine synthesis activity per TH protein.

Original languageEnglish
Pages (from-to)43549-43558
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number50
DOIs
Publication statusPublished - 16-12-2011

Fingerprint

Tyrosine 3-Monooxygenase
Ablation
Dopamine
Genes
Dependovirus
Viruses
Corpus Striatum
Dihydroxyphenylalanine
Injections
Proteins
Axons
Gene Targeting
Presynaptic Terminals
Carisoprodol
Reward
Brain
Homeostasis
Up-Regulation
Cells
Control systems

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tokuoka, Hirofumi ; Muramatsu, Shin Ichi ; Sumi-Ichinose, Chiho ; Sakane, Hiroaki ; Kojima, Masayo ; Aso, Yoshinori ; Nomura, Takahide ; Metzger, Daniel ; Ichinose, Hiroshi. / Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 50. pp. 43549-43558.
@article{335ac08bd59c40a690861e752a35ad93,
title = "Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection",
abstract = "The tyrosine hydroxylase (TH; EC 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. Here, to further explore the regulatory mechanism of dopamine levels by TH in adult mouse brains, we employed a genetic method to inactivate the Th gene in the nigrostriatal projection using the Cre-loxP system. Stereotaxic injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the substantia nigra pars compacta (SNc), where dopaminergic cell bodies locate, specifically inactivated the Th gene. Whereas the number of TH-expressing cells decreased to less than 40{\%} in the SNc 2 weeks after the AAV-Cre injection, the striatal TH protein level decreased to 75{\%}, 50{\%}, and 39{\%} at 2, 4, and 8 weeks, respectively, after the injection. Thus, unexpectedly, the reduction of TH protein in the striatum, where SNc dopaminergic axons innervate densely, was slower than in the SNc. Moreover, despite the essential requirement of TH for dopamine synthesis, the striatal dopamine contents were only moderately decreased, to 70{\%} even 8 weeks after AAV-Cre injection. Concurrently, in vivo synthesis activity of L-dihydroxyphenylalanine, the dopamine precursor, per TH protein level was augmented, suggesting up-regulation of dopamine synthesis activity in the intact nigrostriatal axons. Collectively, our conditional Th gene targeting method demonstrates two regulatory mechanisms of TH in axon terminals for dopamine homeostasis in vivo: local regulation of TH protein amount independent of soma and trans-axonal regulation of apparent L-dihydroxyphenylalanine synthesis activity per TH protein.",
author = "Hirofumi Tokuoka and Muramatsu, {Shin Ichi} and Chiho Sumi-Ichinose and Hiroaki Sakane and Masayo Kojima and Yoshinori Aso and Takahide Nomura and Daniel Metzger and Hiroshi Ichinose",
year = "2011",
month = "12",
day = "16",
doi = "10.1074/jbc.M111.284729",
language = "English",
volume = "286",
pages = "43549--43558",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "50",

}

Tokuoka, H, Muramatsu, SI, Sumi-Ichinose, C, Sakane, H, Kojima, M, Aso, Y, Nomura, T, Metzger, D & Ichinose, H 2011, 'Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection', Journal of Biological Chemistry, vol. 286, no. 50, pp. 43549-43558. https://doi.org/10.1074/jbc.M111.284729

Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection. / Tokuoka, Hirofumi; Muramatsu, Shin Ichi; Sumi-Ichinose, Chiho; Sakane, Hiroaki; Kojima, Masayo; Aso, Yoshinori; Nomura, Takahide; Metzger, Daniel; Ichinose, Hiroshi.

In: Journal of Biological Chemistry, Vol. 286, No. 50, 16.12.2011, p. 43549-43558.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection

AU - Tokuoka, Hirofumi

AU - Muramatsu, Shin Ichi

AU - Sumi-Ichinose, Chiho

AU - Sakane, Hiroaki

AU - Kojima, Masayo

AU - Aso, Yoshinori

AU - Nomura, Takahide

AU - Metzger, Daniel

AU - Ichinose, Hiroshi

PY - 2011/12/16

Y1 - 2011/12/16

N2 - The tyrosine hydroxylase (TH; EC 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. Here, to further explore the regulatory mechanism of dopamine levels by TH in adult mouse brains, we employed a genetic method to inactivate the Th gene in the nigrostriatal projection using the Cre-loxP system. Stereotaxic injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the substantia nigra pars compacta (SNc), where dopaminergic cell bodies locate, specifically inactivated the Th gene. Whereas the number of TH-expressing cells decreased to less than 40% in the SNc 2 weeks after the AAV-Cre injection, the striatal TH protein level decreased to 75%, 50%, and 39% at 2, 4, and 8 weeks, respectively, after the injection. Thus, unexpectedly, the reduction of TH protein in the striatum, where SNc dopaminergic axons innervate densely, was slower than in the SNc. Moreover, despite the essential requirement of TH for dopamine synthesis, the striatal dopamine contents were only moderately decreased, to 70% even 8 weeks after AAV-Cre injection. Concurrently, in vivo synthesis activity of L-dihydroxyphenylalanine, the dopamine precursor, per TH protein level was augmented, suggesting up-regulation of dopamine synthesis activity in the intact nigrostriatal axons. Collectively, our conditional Th gene targeting method demonstrates two regulatory mechanisms of TH in axon terminals for dopamine homeostasis in vivo: local regulation of TH protein amount independent of soma and trans-axonal regulation of apparent L-dihydroxyphenylalanine synthesis activity per TH protein.

AB - The tyrosine hydroxylase (TH; EC 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. Here, to further explore the regulatory mechanism of dopamine levels by TH in adult mouse brains, we employed a genetic method to inactivate the Th gene in the nigrostriatal projection using the Cre-loxP system. Stereotaxic injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the substantia nigra pars compacta (SNc), where dopaminergic cell bodies locate, specifically inactivated the Th gene. Whereas the number of TH-expressing cells decreased to less than 40% in the SNc 2 weeks after the AAV-Cre injection, the striatal TH protein level decreased to 75%, 50%, and 39% at 2, 4, and 8 weeks, respectively, after the injection. Thus, unexpectedly, the reduction of TH protein in the striatum, where SNc dopaminergic axons innervate densely, was slower than in the SNc. Moreover, despite the essential requirement of TH for dopamine synthesis, the striatal dopamine contents were only moderately decreased, to 70% even 8 weeks after AAV-Cre injection. Concurrently, in vivo synthesis activity of L-dihydroxyphenylalanine, the dopamine precursor, per TH protein level was augmented, suggesting up-regulation of dopamine synthesis activity in the intact nigrostriatal axons. Collectively, our conditional Th gene targeting method demonstrates two regulatory mechanisms of TH in axon terminals for dopamine homeostasis in vivo: local regulation of TH protein amount independent of soma and trans-axonal regulation of apparent L-dihydroxyphenylalanine synthesis activity per TH protein.

UR - http://www.scopus.com/inward/record.url?scp=83355166920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83355166920&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.284729

DO - 10.1074/jbc.M111.284729

M3 - Article

C2 - 22027820

AN - SCOPUS:83355166920

VL - 286

SP - 43549

EP - 43558

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 50

ER -