Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice.
The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.
Prosser
H M
HM
Genetics Research, Safety Assessment, Laboratory Animal Sciences, Neurology Centre of Excellence for Drug Discovery, Psychiatry Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom.
Gill
C H
CH
Hirst
W D
WD
Grau
E
E
Robbins
M
M
Calver
A
A
Soffin
E M
EM
Farmer
C E
CE
Lanneau
C
C
Gray
J
J
Schenck
E
E
Warmerdam
B S
BS
Clapham
C
C
Reavill
C
C
Rogers
D C
DC
Stean
T
T
Upton
N
N
Humphreys
K
K
Randall
A
A
Geppert
M
M
Davies
C H
CH
Pangalos
M N
MN
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D002490:Central Nervous System / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D004827:Epilepsy / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D018755:GABA Agonists / Q000494:pharmacology; D018390:Gene Targeting / Q000379:methods; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout / Q000002:abnormalities* / Q000033:anatomy & histology / Q000378:metabolism; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D018080:Receptors, GABA-B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000151:congenital / Q000235:genetics / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018755:GABA Agonists; D012333:RNA, Messenger; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D001418:Baclofen