Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Abstract

Selected mutations in the human ␣4 or ␤2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4 S252F and Chrna4 ؉L264 ) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II͞III cortical pyramidal cells reveal a >20-fold increase in nicotineevoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent ␥-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant ␣4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.cortex ͉ GABAegic interneuron ͉ nicotinic acetylcholine receptor E pilepsy is a common neurological disorder affecting Ϸ1% of the population worldwide. Over the past decade, several idiopathic epilepsies have been identified that show single-gene inheritance. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first idiopathic epilepsy for which specific mutations were described (1). Segregation and subsequent linkage analyses of ADNFLE families led to the assignment of candidate genetic loci and ultimately to the identification of specific mutations. Two of the three loci associated with this partial epilepsy (ENFL1, 20q13.3 and ENFL3, 1p21) map to neuronal nicotinic acetylcholine receptor (nAChR) subunit genes ␣4 and ␤2 (CHRNB2), respectively. A candidate gene for the third locus (ENFL2, 15q24) has not been identified. Considerable clinical and genetic data now provide a strong link between the ADNFLE syndrome and six mutations located within the pore-forming, second transmembrane domain of the ␣4 (S252F, ϩL264, S256L, T265I) and ␤2 (V287L, V287M) nAChR subunits (2), as well as a single mutation located in the third transmembrane domain of the ␤2 subunit (I312M) (3).In most patients with ADNFLE, seizure onset occurs during adolescence with symptoms persisting into adulthood. Affected individuals typically present without adverse neurological symptoms other than seizures, although several reports describe ADNFLE patients with a concomitant history of psychiatric problems (4, 5), cognitive deficits (3), or mental retardation (6). Clinical features of ADNFLE include clusters of brief seizures that initiate during non-rapid eye movement (NREM) sle...

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Enhanced GABAergic inhibition has been shown to promote seizures in a transgenic murine model of frontal lobe epilepsy that is linked to a nicotinic acetylcholine receptor mutation (Klaassen et al, 2006). Neocortical seizures sustained by nicotinic activation are suppressed in these animals by GABA A receptor antagonists, suggesting that seizure onset involves phase resetting of synchronization of principal cells determined by acetylcholine-dependent synchronization of inhibitory cortical networks.…”

α4* Nicotinic Acetylcholine Receptors Modulate Experience-Based Cortical Depression in the Adult Mouse Somatosensory Cortex

“…Furthermore, we show that activating ␣4* nAChRs in vivo by bath application or direct micro-injection of ␣4* nAChR agonist into layer 4 depressed whisker-evoked responses by 30 -50% in control mice, similar to that seen after 3-7 d of whisker deprivation. Indeed, several electrophysiological studies using both human and rodent cortical tissue have shown that ␣4* nAChR activation rapidly depolarizes cortical interneurons, that can be blocked by the ␣4* nAChR antagonist DH␤E (Xiang et al, 1998;Porter et al, 1999;Alkondon et al, 2000;Christophe et al, 2002;Klaassen et al, 2006;Couey et al, 2007;Mann and Mody, 2008). Therefore one possible mechanism underlying the depression of whisker-evoked responses is that ␣4* nAChRs may be enhancing GABAergic inhibition in deprived barrel columns.…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…α4-subunit S284L transgenic rats [135] show a more complete ADNFLE phenotype, with spontaneous attacks during slow-wave sleep, comprising paroxysmal arousals (frightened behavior), dystonic activity, and epileptic wandering. Notably, the pathogenic mechanisms are also different in these models: upon application of nicotine, GABAergic inhibition is increased in frontal cortex of S252F and +L264 knockin mice [133], whereas it is reduced in somatosensory cortex of S284L transgenic rats [135].…”

“…Whereas β2 mutations showed gain of function by increased sensitivity to acetylcholine or slower desensitization [125], the α2 mutation showed gain of function by increased sensitivity to acetylcholine [128]. The α4 mutations S252F and +L264 engineered in knockin mice [133] induced spontaneous seizures of various types, in some cases similar to those of the human phenotype, but no paroxysmal arousal and dystonia-like manifestations that are typical of ADNFLE; α4 subunit knockout mice showed no spontaneous seizures, but had nicotine-induced dystonic attacks [134]. α4-subunit S284L transgenic rats [135] show a more complete ADNFLE phenotype, with spontaneous attacks during slow-wave sleep, comprising paroxysmal arousals (frightened behavior), dystonic activity, and epileptic wandering.…”