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...
Recent evidence indicates that a central bottleneck causes much of the slowing that occurs when two tasks are performed at the same time. This bottleneck might reflect a structural limitation inherent in the cognitive architecture. Alternatively, the bottleneck might reflect strategic (i.e., voluntary) postponement, induced by instructions to emphasize one task over the other. To distinguish structural limitations from strategic postponement, we examine a new paradigm in which subjects are told to place equal emphasis on both tasks and to emit both responses at about the same time. An experiment using this paradigm demonstrated patterns of interference that cannot easily be attributed to strategic postponement, preparation effects, or conflicts in response production. The data conform closely to the predictions of structural central bottleneck models.
Five nicotinic acetylcholine receptor (nAChR) mutations are currently linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The similarity of their clinical symptoms suggests that a common functional anomaly of the mutations underlies ADNFLE seizures. To identify this anomaly, we constructed rat orthologues (S252F, +L264, S256L, V262L, V262M) of the human ADNFLE mutations, expressed them in Xenopus oocytes with the appropriate wild‐type (WT) subunit (α4 or β2), and studied the Ca2+ dependence of their ACh responses. All the mutations significantly reduced 2 mM Ca2+‐induced increases in the 30 μM ACh response (P < 0.05). Consistent with a dominant mode of inheritance, this reduction persisted in oocytes injected with a 1:1 mixture of mutant and WT cRNA. BAPTA injections showed that the reduction was not due to a decrease in the secondary activation of Ca2+‐activated Cl− currents. The S256L mutation also abolished 2 mM Ba2+ potentiation of the ACh response. The S256L, V262L and V262M mutations had complex effects on the ACh concentration‐response relationship but all three mutations shifted the concentration‐response relationship to the left at [ACh]⩾ 30 μM. Co‐expression of the V262M mutation with a mutation (E180Q) that abolished Ca2+ potentiation resulted in 2 mM Ca2+ block, rather than potentiation, of the 30 μM ACh response, suggesting that the ADNFLE mutations reduce Ca2+ potentiation by enhancing Ca2+ block of the α4β2 nAChR. Ca2+ modulation may prevent presynaptic α4β2 nAChRs from overstimulating glutamate release at central excitatory synapses during bouts of synchronous, repetitive activity. Reducing the Ca2+ dependence of the ACh response could trigger seizures by increasing α4β2‐mediated glutamate release during such bouts.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.