Electroencephalographic characterisation of pentylenetetrazole-induced seizures in mice lacking the α4 subunit of the neuronal nicotinic receptor

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) is associated in sonic kindreds with mutations in the genes encoding the alpha4 or beta2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR). Functional characterisation of the described ADNFLE mutations in oocyte preparations has produced conflicting results, with some studies suggesting hypofunction but others showing increased ligand sensitivity or delayed desensitisation. Knockout mice were studied to investigate extreme hypofunction of alpha4 nAChRs in vivo. Mutant (Mt) and control mice underwent epidural electroencephalographic (EEG) recording for 2 h in the untreated state and for 1 h following administration of the gamma-amino butyric acid (GABA) antagonist, pentylenetetrazole (PTZ, 80 mg/kg). No spontaneous seizures occurred and no EEG differences were observed between the genotypes in drug naive mice. Following PTZ, however, Mt mice showed markedly increased mortality compared to controls (85 vs 30%. P < 0.001). Mts also had a greater number of generalised clonic seizures in the first 40 min following injection. In the same period, the EEGs of Mt mice showed an excess of spikes (P = 0.033), multi-spike complexes (P = 0.002) and continuous fast activity (P = 0.017) compared to controls. These findings demonstrate that intact alpha4 nAChR subunits provide significant in vivo protection against the proconvulsant effects of GABA antagonism. (C) 2003 Elsevier Science Ltd. All rights reserved.