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The Journal of Neuroscience, June 1, 1998, 18(11):4119-4132
Modulation of Rat Rotational Behavior by Direct Gene Transfer of
Constitutively Active Protein Kinase C into Nigrostriatal Neurons
Song
Song1,
Yaming
Wang1,
Sun-Yung
Bak1,
Matthew J.
During2,
John
Bryan1,
Oliver
Ashe1,
Donna B.
Ullrey1,
Laura E.
Trask1,
Frederick D.
Grant1,
Karen L.
O'Malley3,
Heimo
Riedel4,
David S.
Goldstein5,
Kim A.
Neve6,
Gerald J.
LaHoste7,
John F.
Marshall7,
John W.
Haycock8,
Rachael L.
Neve9, 10, and
Alfred I.
Geller1, 10
1 Division of Endocrinology, Children's Hospital,
Boston, Massachusetts 02115, 2 Departments of Surgery and
Medicine, Yale University School of Medicine, New Haven, Connecticut
06510, 3 Department of Anatomy and Neurobiology, Washington
University School of Medicine, St. Louis, Missouri 63110, 4 Department of Biological Sciences, Wayne State
University, Detroit, Michigan 48202, 5 Clinical
Neuroscience Branch, National Institute of Neurological Disorders and
Stroke, National Institutes of Health, Bethesda, Maryland 20892, 6 Research Service, Veterans Affairs Medical Center,
Portland, Oregon 97201, 7 Department of Psychobiology,
University of California, Irvine, California 92689, 8 Department of Biochemistry, Louisiana State University
Medical Center, New Orleans, Louisiana, 70119, 9 Molecular
Neurogenetics Laboratory, McLean Hospital, Belmont, Massachusetts
02178, and 10 Program in Neuroscience, Harvard Medical
School, Boston, Massachusetts 02115
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 PKC II (Pkc ) were developed. Pkc exhibited a constitutively active protein kinase activity with a substrate specificity similar to that of rat brain PKC.
As demonstrated in cultured sympathetic neurons, Pkc 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 pkc 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 Pkc, 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.
Key words:
genetic intervention; herpes simplex virus type 1 vectors; protein kinase C; nigrostriatal neurons; motor behavior; basal
ganglia
Copyright © 1998 Society for Neuroscience 0270-6474/98/18114119-14$05.00/0
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