title: Developmental alterations of the septohippocampal cholinergic projection in a lissencephalic mouse model.
abstract: LIS1 is one of principal genes related with Type I lissencephaly, a severe human brain malformation characterized by abnormal neuronal migration in the cortex. The LIS1 gene encodes a brain-specific 45kDa non-catalytic subunit of platelet-activating factor (PAF) acetylhydrolase-1b (PAFAH1b), an enzyme that inactivates the PAF. We have studied the role of Lis1 using a Lis1/sLis1 murine model, which has deleted the first coding exon from Lis1 gene. Homozygous mice are not viable but heterozygous have shown a delayed corticogenesis and neuronal dysplasia, with enhanced cortical excitability. Lis1/sLis1 embryos also exhibited a delay of cortical innervation by the thalamocortical fibers. We have explored in Lis1/sLis1 mice anomalies in forebrain cholinergic neuron development, which migrate from pallium to subpallium, and functionally represent the main cholinergic input to the cerebral cortex, modulating cortical activity and facilitating attention, learning, and memory. We hypothesized that primary migration anomalies and/or disorganized cortex could affect cholinergic projections from the basal forebrain and septum in Lis1/sLis1 mouse. To accomplish our objective we have first studied basal forebrain neurons in Lis1/sLis1 mice during development, and described structural and hodological differences between wild-type and Lis1/sLis1 embryos. In addition, septohippocampal projections showed altered development in mutant embryos. Basal forebrain abnormalities could contribute to hippocampal excitability anomalies secondary to Lis1 mutations and may explain the cognitive symptoms associated to cortical displasia-related mental diseases and epileptogenic syndromes.
authors.affiliation: Instituto de Neurociencias, UMH-CSIC, Campus de San Juan, E-03550 Alicante, Spain. Electronic address: r.garlo@umh.es.
authors.forename: Raquel
authors.initials: R
authors.lastname: Garcia-Lopez
authors.affiliation: Instituto de Neurociencias, UMH-CSIC, Campus de San Juan, E-03550 Alicante, Spain. Electronic address: apombero@umh.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Pombero
authors.affiliation: Instituto de Neurociencias, UMH-CSIC, Campus de San Juan, E-03550 Alicante, Spain. Electronic address: edominguez@umh.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Dominguez
authors.affiliation: Instituto de Neurociencias, UMH-CSIC, Campus de San Juan, E-03550 Alicante, Spain. Electronic address: emilio.geijo@umh.es.
authors.forename: Emilio
authors.initials: E
authors.lastname: Geijo-Barrientos
authors.affiliation: Instituto de Neurociencias, UMH-CSIC, Campus de San Juan, E-03550 Alicante, Spain; IMIB-Arrixaca, Universidad de Murcia, Spain; Centro de Investigación Biomédica en Red en el Area de Salud Mental (CIBERSAM), Universidad de Murcia, Spain. Electronic address: smartinez@umh.es.
authors.forename: Salvador
authors.initials: S
authors.lastname: Martinez
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D054082:Lissencephaly / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009434:Neural Pathways / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D020665:Septum of Brain / Q000196:embryology / Q000254:growth & development / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C516550:Pafah1b1 protein, rat; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000110:Acetylcholinesterase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: Basal forebrain; Cholinergic neurons; LIS1; Septohippocampal projection