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 journalArticlepeer-review

21 Citations (Scopus)


The tyrosine hydroxylase (TH; EC 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
Issue number50
Publication statusPublished - 16-12-2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection'. Together they form a unique fingerprint.

Cite this