Down-regulation of GABA-transporter function by hippocampal translation products: its possible role in epilepsy.
The genetically epileptic mouse strain (El) is used as a model for human temporal lobe epilepsy. To address the question of whether altered function of the neuronal GABA transporter GAT1 is involved in the pathology of epilepsy of El mice, we expressed in Xenopus oocytes cloned GAT1 of mouse brain by injection of complementary ribonucleic acid (cRNA) and co-injected messenger ribonucleic acid (mRNA) isolated from the hippocampus of non-epileptic control mother strain (ddY) mice and from El mice. GABA transporter activity was investigated by measurements of [(3)H]-GABA uptake as well as by steady-state and transient current measurements under voltage clamp.Co-injection of hippocampal mRNA into oocytes reduced GAT1-mediated transport. This effect was more pronounced for mRNA from ddY mice than for that from El mice that never experienced seizures, El(-), and being absent for mRNA from El mice that have had high seizure experience, El(+). The pronounced inhibition of GABA transport after injection of mRNA from the ddY strain results from reduced expression of functional GAT1, but to about one third also from a reduced GABA translocation rate. The reduced translocation can be attributed to a reduced forward rate of a step associated with extracellular Na(+) binding. If the results can be applied to the mouse brain, we may hypothesise that in ddY mice some GAT down-regulating factor translated from hippocampal mRNA may be involved to keep GAT1 activity low, and hence GABA concentration in synaptic cleft high. In El(-) mice such regulatory mechanism may be reduced or counteracted by another unknown factor present in El(-) brain. The repeated seizure experience in El(+) mice enhances this compensatory effect.
Fueta
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Max-Planck Institut für Biophysik, Marie-Curie Str 15, 60439 Frankfurt am Main, Germany.
Vasilets
L A
LA
Takeda
K
K
Kawamura
M
M
Schwarz
W
W
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D027361:Organic Anion Transporters; D018408:Patch-Clamp Techniques / Q000379:methods; D018075:RNA, Complementary / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D014316:Tritium / Q000378:metabolism; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D018075:RNA, Complementary; D012333:RNA, Messenger; C493413:SLC6A1 protein, human; C493414:Slc6a1 protein, mouse; D014316:Tritium; D005680:gamma-Aminobutyric Acid; D007608:Kainic Acid