Modulation of rat rotational behavior by direct gene transfer of constitutively active protein kinase C into nigrostriatal neurons

Song Song, Yaming Wang, Sun Yung Bak, Matthew J. During, John Bryan, Oliver Ashe, Donna B. Ullrey, Laura E. Trask, Frederick D. Grant, Karen L. O'Malley, Heimo Riedel, David S. Goldstein, Kim Neve, Gerald J. Lahoste, John F. Marshall, John W. Haycock, Rachael L. Neve, Alfred I. Geller

Research output: Contribution to journalArticle

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Abstract

The modulation of motor behavior by protein kinase C (PKC) signaling pathways in nigrostriatal neurons was examined by using a genetic intervention approach. Herpes simplex virus type 1 (HSV-1) vectors that encode a catalytic domain of rat PKCβII (PkcΔ) were developed. PkcΔ exhibited a constitutively active protein kinase activity with a substrate specificity similar to that of rat brain PKC. As demonstrated in cultured sympathetic neurons, PkcΔ caused a long-lasting, activation-dependent increase in neurotransmitter release. In the rat brain, microinjection of HSV-1 vectors that contain the tyrosine hydroxylase promoter targeted expression to dopaminergic nigrostriatal neurons. Expression of pkcΔ in a small percentage of nigrostriatal neurons (~0.1-2%) was sufficient to produce a long-term (≤1 month) change in apomorphine-induced rotational behavior. Nigrostriatal neurons were the only catecholaminergic neurons that contained PkcΔ, and the amount of rotational behavior was correlated with the number of affected nigrostriatal neurons. The change in apomorphine- induced rotational behavior was blocked by a dopamine receptor antagonist (fluphenazine). D2-like dopamine receptor density was increased in those regions of the striatum innervated by the affected nigrostriatal neurons. Therefore, this strategy enabled the demonstration that a PKC pathway or PKC pathways in nigrostriatal neurons modulate apomorphine-induced rotational behavior, and altered dopaminergic transmission from nigrostriatal neurons appears to be the affected neuronal physiology responsible for the change in rotational behavior.

Original languageEnglish (US)
Pages (from-to)4119-4132
Number of pages14
JournalJournal of Neuroscience
Volume18
Issue number11
Publication statusPublished - Jun 1 1998
Externally publishedYes

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Keywords

  • Basal ganglia
  • Genetic intervention
  • Herpes simplex virus type 1 vectors
  • Motor behavior
  • Nigrostriatal neurons
  • Protein kinase C

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Song, S., Wang, Y., Bak, S. Y., During, M. J., Bryan, J., Ashe, O., ... Geller, A. I. (1998). Modulation of rat rotational behavior by direct gene transfer of constitutively active protein kinase C into nigrostriatal neurons. Journal of Neuroscience, 18(11), 4119-4132.