Experimental parkinsonism is associated with increased pallidal GAD gene expression and is reversed by site-directed antisense gene therapy
✍ Scribed by Jay S. Schneider; Timothy V. Wade
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 259 KB
- Volume
- 18
- Category
- Article
- ISSN
- 0885-3185
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✦ Synopsis
Abstract
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