Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats.
Local application of GABA-potentiating agents can prevent or reduce the development and maintenance of behavioral seizures induced by limbic kindling in rats. Microinjection and lesion studies suggest that the transition zone between anterior and posterior piriform cortex (PC), termed here central PC, is a potential target for transplantation of GABA-producing cells. In the present study, we transplanted conditionally immortalized mouse cortical neurons, engineered with the GABA-synthesizing enzyme GAD(65), to the central PC of rats. Suspensions of 1.5 x 10(5) cells in 1 microl were transplanted bilaterally. Control animals received transplantation of beta-galactosidase (beta-gal)-expressing cells. All rats were subsequently kindled through a chronically implanted electrode placed in the basolateral amygdala. The pre- and postkindling threshold currents for eliciting behavioral seizures were determined before and after kindling. We found the prekindling partial seizure threshold to be significantly increased by about 200% in the rats that received the GABA-producing cells compared to rats receiving beta-gal-producing transplants. After kindling, the seizure threshold tended to be higher by 100% in rats that received GABA-producing cells, although the difference from controls was not statistically significant. GABA-producing transplants had no significant effect on the rate of amygdala kindling, but the latency to the first generalized seizure during kindling was significantly increased in animals receiving GABA-producing cells. The transplanted cells showed long-term GAD(65) expression as verified immunohistologically after termination of the experiments. The findings substantiate and extend previous findings that the central PC is part of the anatomical substrate that facilitates propagation from partial to generalized seizures. The data demonstrate that genetically engineered cells have the potential to raise seizure thresholds when transplanted to the central PC.
Gernert
Manuela
M
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine Hannover, Bünteweg 17, Hannover, Germany. manuela.gernert@tiho-hannover
Thompson
Kerry W
KW
Löscher
Wolfgang
W
Tobin
Allan J
AJ
D000679:Amygdala / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000601:surgery; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D004827:Epilepsy / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007696:Kindling, Neurologic; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D009833:Olfactory Pathways / Q000166:cytology / Q000601:surgery; D051381:Rats; D017208:Rats, Wistar; D013995:Time; D019076:Transgenes; D016896:Treatment Outcome; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis*
D007527:Isoenzymes; D005680:gamma-Aminobutyric Acid; D001616:beta-Galactosidase; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2