title: Etiology of a genetically complex seizure disorder in Celf4 mutant mice.
abstract: Mice deficient for the gene encoding the RNA-binding protein CELF4 (CUGBP, ELAV-like family member 4) have a complex seizure phenotype that includes both convulsive and non-convulsive seizures, depending upon gene dosage and strain background, modeling genetically complex epilepsy. Invertebrate CELF is associated with translational control in fruit fly ovary epithelium and with neurogenesis and neuronal function in the nematode. Mammalian CELF4 is expressed widely during early development, but is restricted to the central nervous system in adults. To better understand the etiology of the seizure disorder of Celf4 deficient mice, we studied seizure incidence with spatial and temporal conditional knockout Celf4 alleles. For convulsive seizure phenotypes, it is sufficient to delete Celf4 in adulthood at the age of 7 weeks. This timing is in contrast to absence-like non-convulsive seizures, which require deletion before the end of the first postnatal week. Interestingly, selective deletion of Celf4 from cerebral cortex and hippocampus excitatory neurons, but not from inhibitory neurons, is sufficient to lower seizure threshold and to promote spontaneous convulsions. Correspondingly, Celf4 deficient mice have altered excitatory, but not inhibitory, neurotransmission as measured by patch-clamp recordings of cortical layer V pyramidal neurons. Finally, immunostaining in conjunction with an inhibitory neuron-specific reporter shows that CELF4 is expressed predominantly in excitatory neurons. Our results suggest that CELF4 plays a specific role in regulating excitatory neurotransmission. We posit that altered excitatory neurotransmission resulting from Celf4 deficiency underlies the complex seizure disorder in Celf4 mutant mice.
authors: The Jackson Laboratory, Bar Harbor, ME 04609-1500, USA.
authors: J L
authors: JL
authors: Wagnon
authors: C L
authors: CL
authors: Mahaffey
authors: W
authors: W
authors: Sun
authors: Y
authors: Y
authors: Yang
authors: H-T
authors: HT
authors: Chao
authors: W N
authors: WN
authors: Frankel
mesh_terms: D000367:Age Factors; D000818:Animals; D000067878:CELF Proteins; D003423:Critical Period, Psychological; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004827:Epilepsy / Q000145:classification / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics*; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000235:genetics*; D012640:Seizures / Q000145:classification / Q000235:genetics*
chemical_list: D000067878:CELF Proteins; C470022:Celf4 protein, mouse; D016601:RNA-Binding Proteins