Two mutations linked to nocturnal frontal lobe epilepsy cause use-dependent potentiation of the nicotinic ACh response


Corresponding author B. N. Cohen: Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA. Email:


  • 1We constructed rat homologues (S252F and +L264) of two human α4 nicotinic mutations - α4(S248F) and α4(777ins3) - that have been linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and co-expressed them with wild-type rat β2 subunits in Xenopus oocytes.
  • 2The S252F and +L264 mutations had three common effects on the ACh response. First, they caused use-dependent potentiation of the response during a train of brief 100 nm ACh pulses. Second, they delayed the rise times of the 5–15 nm (+L264) and 30 nm (S252F) ACh responses. Third, they reduced extracellular Ca2+-induced increases in the 30 μm ACh response.
  • 3Beside these shared effects, the S252F mutation also reduced the channel burst duration measured from voltage-jump relaxations, enhanced steady-state desensitization and reduced the single-channel conductance. In contrast, the +L264 mutation prolonged the channel burst duration, did not affect desensitization and slightly increased single-channel conductance. Neither mutation affected the number of surface receptors measured by antibody binding but the S252F mutation reduced the maximum ACh response.
  • 4The ACh concentration dependence of use-dependent potentiation and the delay in the rising phase of the mutant ACh response suggest that these effects are caused by a slow unblocking of the closed mutant receptors. Use-dependent potentiation of the mutant response during a series of high-frequency cholinergic inputs to the presynaptic terminal could trigger ADNFLE seizures by suddenly increasing nicotinic-mediated transmitter release.