Antisense oligonucleotide to GABAA receptor gamma 2 subunit induces loss of neurones in rat hippocampus.
The binding site for 1,4-benzodiazepines in the brain is part of the hetero-oligomeric gamma-aminobutyric acid (GABA)A receptor complex which regulates a chloride ion channel. The presence of the gamma 2 subunit in the complex is necessary for the binding of benzodiazepines to their binding site. This study demonstrates a reduction of benzodiazepine receptor radioligand binding by 43% compared to control following infusion of phosphorothioate antisense oligodeoxynucleotide to gamma 2 subunit into rat hippocampus. Reduction of benzodiazepine binding sites was paralleled by a decrease in [35S]tert-butyl-bicyclo-phosphorothionate ([35S]TBPS) binding (51%) and [3H]muscimol binding (37%), indicating a reduction in the number of GABAA receptors. Changed macroscopic appearance, reduced protein content and severe loss of neurones in antisense-treated hippocampi suggests that the reduced formation of GABAA receptors leads to neuronal cell death.
Karle
J
J
Research Institute of Biological Psychiatry, St. Hans Psychiatric Hospital, Roskilde, Denmark.
Witt
M R
MR
Nielsen
M
M
D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000502:physiology; D001569:Benzodiazepines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002452:Cell Count; D003292:Convulsants / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D008969:Molecular Sequence Data; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016376:Oligonucleotides, Antisense; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics* / Q000648:ultrastructure; D013462:Sulfur Radioisotopes; D014316:Tritium
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018755:GABA Agonists; D018757:GABA Modulators; D016376:Oligonucleotides, Antisense; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; D014316:Tritium; D001569:Benzodiazepines; D009118:Muscimol; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate