The multifaceted role of inhibition in epilepsy: seizure-genesis through excessive GABAergic inhibition in autosomal dominant nocturnal frontal lobe epilepsy.
OBJECTIVE
While epilepsy describes a heterogeneous array of syndromes, the conventional view is that there is a common underlying failure in the ability of GABAergic inhibition to overcome excessive synaptic excitation. This review explores the possibility that enhanced GABAergic inhibition in the neocortex could also be proepileptogenic.


RESULTS
Recently, two mouse strains carrying mutant alleles of the alpha4 subunit of the nicotinic acetylcholine receptor that are associated with autosomal dominant nocturnal frontal lobe epilepsy have been found to show spontaneous seizures. Recordings from neocortical pyramidal neurons in vitro show that the autosomal dominant nocturnal frontal lobe epilepsy mutations are associated with large selective increases in nicotine-evoked GABAergic inhibition, which may be key factor in epileptogenesis, as the seizures in vivo are blocked by subconvulsive doses of the GABAA receptor antagonist, picrotoxin.


CONCLUSIONS
The precise links between the observed gain of neocortical inhibition and development of seizures in autosomal dominant nocturnal frontal lobe epilepsy mice remain unknown. Recent insights into the functional properties of cortical GABAergic circuits, however, suggest several possible pathways to be explored, whose elucidation could enable selective therapeutic interventions.
Mann
Edward O
EO
Department of Neurology, The David Geffen School of Medicine at the University of California, Los Angeles, California 90095-733522, USA. mody@ucla.edu
Mody
Istvan
I
D000818:Animals; D025063:Chromosome Disorders / Q000235:genetics; D021081:Chronobiology Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D017034:Epilepsy, Frontal Lobe / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D051379:Mice; D009433:Neural Inhibition / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D005680:gamma-Aminobutyric Acid