Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

Abstract

Adhesion molecules play major roles in cell proliferation, migration, survival, neurite outgrowth and synapse formation during nervous system development and in adulthood. The neural cell adhesion molecule L1 contributes to these functions during development and in synapse formation and synaptic plasticity after trauma in adulthood. Mutations of L1 in humans result in L1 syndrome, which is associated with mild-to-severe brain malformations and mental disabilities. Furthermore, mutations in the extracellular domain were shown to cause a severe phenotype more often than mutations in the intracellular domain. To explore the outcome of a mutation in the extracellular domain, we generated mice with disruption of the dibasic sequences RK and KR that localize to position 858RKHSKR863 in the third fibronectin type III domain of murine L1. These mice exhibit alterations in exploratory behavior and enhanced marble burying activity. Mutant mice display higher numbers of caspase 3-positive neurons, a reduced number of principle neurons in the hippocampus, and an enhanced number of glial cells. Experiments suggest that disruption of the dibasic sequence in L1 results in subtle impairments in brain structure and functions leading to obsessive-like behavior in males and reduced anxiety in females.

Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities

“…This distinguishes L1/687 mice from L1/858-863 mice, which also lack L1-70. L1/858-863 mice were socially normal, but L1/858-863 males buried more marbles than WT males [57]. In summary, the lack of L1-70 is not responsible for reduced social interest of L1/687 females nor does it lead to autism-like or compulsive-like behavior or changes in anxiety.…”

“…The motor coordination of 8-month-old L1/687 males was reduced, while 8-month-old L1/687 females showed better coordination compared to the wild-type females, revealing gender differences for L1/687 mice. Furthermore, male and female mice with disruption of the dibasic sequences in the third FNIII homologous repeat of L1 (L1/858-863 mice), which also lack the L1-70 fragment [53], showed normal velocity and distance moved in the open field, and L1/858-863 females were less anxious [57]. These results support the notion that different hormone levels in males and females could underlie the differences in the behavior of L1/687 males and females.…”

“…The same microscope and software were used to measure average thickness of hippocampal principal cell layers and corpus callosum. To estimate cell densities (number of cells per volume), the optical dissector method was used, as described [57]. The counts were performed under an Axioskop microscope (Zeiss) equipped with a motorized stage and Neurolucida software-controlled computer system (MicroBrightField Europe).…”

Interaction of L1CAM with LC3 Is Required for L1-Dependent Neurite Outgrowth and Neuronal Survival

“…L1-70 contributes to neuritogenesis, neuronal migration and survival, astrogliosis, gene expression, and mitochondrial homeostasis [24,36,[40][41][42]47,48]. Of note, the upregulation of L1-70 expression in a mouse model of Alzheimer's disease by parabiosis with a wild-type mouse reduced amyloid-β plaques, and mutant mice lacking L1-70 are abnormal in behavior [49,50].…”