Pathfinding errors of corticospinal axons in neural cell adhesion molecule-deficient mice.

The neural cell adhesion molecule (NCAM) is a cell recognition molecule of the Ig superfamily implicated in cell migration, myelination, and synaptic plasticity, as well as elongation, fasciculation, and pathfinding of axons. Here, we used NCAM-deficient mice to investigate the role of NCAM in the development of the corticospinal tract. We demonstrate severe hypoplasia of the corticospinal tract in adult NCAM mutants. Anterograde tracing of the tract of early postnatal NCAM mutants revealed pronounced pathfinding errors of corticospinal axons. At the pyramidal decussation of mutant mice, some corticospinal axons either stayed ventrally and extended laterally, or axons turned dorsally, but instead of growing to the contralateral dorsal column, a significant fraction of axons projected ipsilaterally. We also observed that corticospinal axons of NCAM mutants entered the pyramidal decussation significantly later than axons of wild-type littermates. Our observations thus demonstrate a critical role of NCAM for the formation of this major axon tract.

Altered expression of CHL1 by glial cells in response to optic nerve injury and intravitreal application of fibroblast growth factor-2.

The close homologue of L1 (CHL1) is a member of the L1 family of cell recognition molecules. The protein is expressed by a variety of nerve cell types and subpopulations of glial cells in vivo and promotes elongation of neurites and survival of nerve cells in vitro. Here we demonstrate that glial cells up-regulate expression of CHL1 in response to an intraorbital crush of the adult mouse optic nerve. We also demonstrate that a single intravitreal application of fibroblast growth factor-2 (FGF-2) increases expression of CHL1 in retinal astrocytes and Müller cells. Elevated expression of CHL1 by glial cells in injured optic nerves and astrocytes and Müller cells in FGF-2-treated retinas suggests a role of the protein in the lesioned central nervous system. Results also suggest that trophic factors might exert part of their biological function by modifying expression of cell recognition molecules.

Reduced GABAergic transmission and number of hippocampal perisomatic inhibitory synapses in juvenile mice deficient in the neural cell adhesion molecule L1.

Cell adhesion molecules have been implicated in neural development and hippocampal synaptic plasticity. Here, we investigated the role of the neural cell adhesion molecule L1 in regulation of basal synaptic transmission and plasticity in the CA1 area of the hippocampus of juvenile mice. We show that theta-burst stimulation (TBS) and pairing of low-frequency presynaptic stimulation with depolarization of postsynaptic CA1 pyramidal cells induced similar levels of LTP in L1-deficient and wild-type mice. The basal excitatory synaptic transmission and density of asymmetric excitatory synapses in the stratum radiatum were also normal in L1-deficient mice. Since L1 is expressed not only by principal cells but also by inhibitory interneurons, we recorded inhibitory postsynaptic currents (IPSCs) evoked in CA1 pyramidal cells by minimal stimulation of perisomatic interneurons. L1-deficient mice showed a reduction in the mean amplitude of putative unitary IPSCs, higher values of the coefficient of amplitude variation, higher number of failures in transmitter release, and a reduction in frequency but not amplitude of miniature IPSCs. The use-dependent modulation of inhibitory transmission by paired-pulse or short tetanic stimulation was, however, normal in L1-deficient mice. The physiological abnormalities correlated with a strong reduction in the density of inhibitory active zones, indicating that L1 is involved in establishing inhibitory perisomatic synapses in the hippocampus.

CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior.

Investigation of MR patients with 3p aberrations led to the identification of the translocation breakpoint in intron five of the neural Cell Adhesion L1-Like (CALL or CHL1) gene in a man with non-specific mental retardation and 46,Y, t(X;3)(p22.1;p26.3). The Xp breakpoint does not seem to affect a known or predicted gene. Moreover, a fusion transcript with the CALL gene could not be detected and no mutations were identified on the second allele. CALL is highly expressed in the central and peripheral nervous system, like the mouse ortholog 'close homolog to L1' (Chl1). Chl1 expression levels in the hippocampus of Chl1(+/-) mice were half of those obtained in wild-type littermates, reflecting a gene dosage effect. Timm staining and synaptophysin immunohistochemistry of the hippocampus showed focal groups of ectopic mossy fiber synapses in the lateral CA3 region, outside the trajectory of the infra-pyramidal mossy fiber bundle in Chl1(-/-) and Chl1(+/-) mice. Behavioral assessment demonstrated mild alterations in the Chl1(-/-) animals. In the probe trial of the Morris Water Maze test, Chl1(-/-) mice displayed an altered exploratory pattern. In addition, these mice were significantly more sociable and less aggressive as demonstrated in social exploration tests. The Chl1(+/-) mice showed a phenotypic spectrum ranging from wild-type to knockout behavior. We hypothesize that a 50% reduction of CALL expression in the developing brain results in cognitive deficits. This suggests that the CALL gene at 3p26.3 is a prime candidate for an autosomal form of mental retardation. So far, mutation analysis of the CALL gene in patients with non-specific MR did not reveal any disease-associated mutations.