Developmental alterations of the septohippocampal cholinergic projection in a lissencephalic mouse model

Abstract

LIS1 is one of principal genes relatedwith Type I lissencephaly, a severe human brain malformation characterized by abnormal neuronal migration in the cortex. The LIS1 gene encodes a brain-specific 45 kDa 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. Homozygousmice 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 septumin Lis1/sLis1 mouse. To accomplish our objectivewe 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 Lis1mutations and may explain the cognitive symptoms associated to cortical displasia-relatedmental diseases and epileptogenic syndromes