K. Thompson et al., Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures, EXP NEUROL, 161(2), 2000, pp. 481-489
Transplantation of genetically engineered cells can provide sustained focal
delivery of naturally occurring molecules, including neurotransmitters and
growth factors. We have engineered immortalized mouse cortical neurons and
glia to deliver GABA by driving GAD(65) expression. Engineered cell lines
showed GAD(65) mRNA expression, enzymatic activity and GABA release. In vit
ro, basal flux of GABA was approximately 20% of total cellular GABA. We tra
nsplanted these GABA-producing cells bilaterally into either the anterior o
r the posterior substantia nigra of 43 rats. The rats were subsequently kin
dled through an electrode placed in the entorhinal cortex. GABA-producing c
ells, but not beta-galactosidase-producing cells, affected kindling rates.
The number of stimulations needed to reach the first stage-5 seizure and to
achieve full kindling differed significantly between the anterior and post
erior transplantation sites when GAD(65)-producing cells were transplanted
but not when beta-galactosidase-producing cells were transplanted. Our data
show that transplanted engineered cells can make and release GABA at physi
ologically meaningful concentrations. (C) 2000 Academic Press.