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Experimental parkinsonism is associated with increased pallidal GAD gene expression and is reversed by site‐directed antisense gene therapy
Author(s) -
Schneider Jay S.,
Wade Timothy V.
Publication year - 2003
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.10316
Subject(s) - parkinsonism , mptp , glutamate decarboxylase , globus pallidus , gabaergic , asymptomatic , biology , medicine , endocrinology , basal ganglia , neuroscience , parkinson's disease , central nervous system , enzyme , biochemistry , disease , inhibitory postsynaptic potential
The levels of mRNA encoding the two isoforms of glutamic acid decarboxylase (GAD 65 and GAD 67 ) were measured throughout the pallidal complex in normal and acutely (i.e., 1 month duration) and chronically (i.e., 5 years duration) parkinsonian 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) ‐treated monkeys as well as in monkeys exposed to MPTP but asymptomatic for parkinsonism. GAD 65 mRNA labeling was modestly increased in the mid/caudal internal globus pallidus (GPi) but not in the external globus pallidus (GPe) in parkinsonian monkeys, compared with normal and asymptomatic monkeys. GAD 67 mRNA expression was highly increased in the mid/caudal GPi, and modestly increased in the GPe in parkinsonian monkeys compared with normal and asymptomatic animals. Infusion of GAD 67 antisense oligodeoxynucleotides bilaterally into the GPi resulted in a transient reversal of akinesia and bradykinesia that was not produced by infusion of missense oligodeoxynucleotides. These data emphasize the role of GAD enzyme (particularly GAD 67 ) and GABA in the GPi for the expression of parkinsonian motor signs and suggest that selective manipulation of GABAergic neurotransmission in the GPi may have therapeutic potential for treating parkinsonism. © 2002 Movement Disorder Society