title: Gene transfer of constitutively active protein kinase C into striatal neurons accelerates onset of levodopa-induced motor response alterations in parkinsonian rats.
abstract: Alterations in motor response that complicate levodopa treatment of Parkinson's disease appear to involve sensitization of striatal ionotropic glutamate receptors. Since protein kinase C (PKC)-mediated phosphorylation regulates glutamatergic receptors of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) subtype and has been linked to several forms of behavioral plasticity, activation of PKC signaling in striatal spiny neurons may also contribute to the motor plasticity changes associated with chronic levodopa therapy. To evaluate this possibility, we sought to augment PKC signaling by using Herpes Simplex Virus type 1 vectors (pHSVpkcDelta) to directly transfer the catalytic domain of the PKCbetaII gene into striatal neurons of parkinsonian rats. Microinjection of pHSVpkcDelta vectors lead to the persistent expression of PkcDelta (35% loss over 21 days) in medium spiny neurons together with an increase in serine 831 phosphorylation on AMPA receptor GluR1 subunits and hastened the appearance of the shortened response duration produced by chronic levodopa treatment (P<0.05). In pHSVpkcDelta-infected animals, intrastriatal injection of the PKC inhibitor NPC-15437 (1.0 microg) attenuated both the increased GluR1 phosphorylation (P<0.01) and the accelerated onset of the levodopa-induced response modifications (P<0.01). However, in rats that received levodopa treatment for 21 days without the gene transfer, intrastriatal NPC-15437 had no effect on the response shortening or on GluR1 S831 phosphorylation. The results suggest that an increase in PKC-mediated signaling, including, in part, phosphorylation of AMPA receptors, on striatal spiny neurons may be sufficient to promote the initial appearance, but not necessary the ultimate expression, of the levodopa-induced motor response changes occurring in a rodent model of the human motor complication syndrome.
authors.affiliation: Department of Psychology, Sloan 224, Central Michigan University, Mount Pleasant, MI 48859, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Oh
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Geller
authors.forename: Guo rong
authors.initials: Gr
authors.lastname: Zhang
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Chase
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022761:Gene Transfer, Horizontal / Q000502:physiology; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human; D007150:Immunohistochemistry; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D020734:Parkinsonian Disorders / Q000201:enzymology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D004791:Enzyme Inhibitors; D007980:Levodopa; D010880:Piperidines; D011493:Protein Kinase C; D018091:Receptors, AMPA; C069701:NPC 15437