UMLS:C0004352 - FACTA Search

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Query: UMLS:C0004352 (autism)
32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rett syndrome (RTT) is an autism spectrum disorder that results from mutations in the transcriptional regulator methyl-CpG binding protein 2 (MECP2). In the present work, we demonstrate that MeCP2 deficiency disrupts the establishment of neural connections before synaptogenesis. Using both in vitro and in vivo approaches, we identify dynamic alterations in the expression of class 3 semaphorins that are accompanied by defects in axonal fasciculation, guidance, and targeting with MeCP2 deficiency. Olfactory axons from Mecp2 mutant mice display aberrant repulsion when co-cultured with mutant olfactory bulb explants. This defect is restored when mutant olfactory axons are co-cultured with wild type olfactory bulbs. Thus, a non-cell autonomous mechanism involving Semaphorin 3F function may underlie abnormalities in the establishment of connectivity with Mecp2 mutation. These findings have broad implications for the role of MECP2 in neurodevelopment and RTT, given the critical role of the semaphorins in the formation of neural circuits.
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PMID:MeCP2 deficiency disrupts axonal guidance, fasciculation, and targeting by altering Semaphorin 3F function. 1962 41

Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G-protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive-compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system.
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PMID:Neural cell adhesion molecules belonging to the family of leucine-rich repeat proteins. 2530 Jan 43

Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment.
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PMID:21q21 deletion involving NCAM2: report of 3 cases with neurodevelopmental disorders. 2546 10

The gene encoding the neural cell adhesion molecule Contactin-6 (Cntn6 a.k.a. NB-3) has been implicated as an autism risk gene, suggesting that its mutation is deleterious to brain development. Due to its GPI-anchor at Cntn6 may exert cell adhesion/receptor functions in complex with other membrane proteins, or serve as a ligand. We aimed to uncover novel phenotypes related to Cntn6 functions during development in the cerebral cortex of adult Cntn6(-/-) mice. We first determined Cntn6 protein and mRNA expression in the cortex, thalamic nuclei and the hippocampus at P14, which decreased specifically in the cortex at adult stages. Neuroanatomical analysis demonstrated a significant decrease of Cux1+ projection neurons in layers II-IV and an increase of FoxP2+ projection neurons in layer VI in the visual cortex of adult Cntn6(-/-) mice compared to wild-type controls. Furthermore, the number of parvalbumin+ (PV) interneurons was decreased in Cntn6(-/-) mice, while the amount of NPY+ interneurons remained unchanged. In the hippocampus the delineation and outgrowth of mossy fibers remained largely unchanged, except for the observation of a larger suprapyramidal bundle. The observed abnormalities in the cerebral cortex and hippocampus of Cntn6(-/-) mice suggests that Cntn6 serves developmental functions involving cell survival, migration and fasciculation. Furthermore, these data suggest that Cntn6 engages in both trans- and cis-interactions and may be involved in larger protein interaction networks.
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PMID:Developmental role of the cell adhesion molecule Contactin-6 in the cerebral cortex and hippocampus. 2693 65

Membrane excitability in the axonal growth cones of embryonic neurons influences axon growth. Voltage-gated K⁺ (Kv) channels are key factors in controlling membrane excitability, but whether they regulate axon growth remains unclear. Here, we report that Kv3.4 is expressed in the axonal growth cones of embryonic spinal commissural neurons, motoneurons, dorsal root ganglion neurons, retinal ganglion cells, and callosal projection neurons during axon growth. Our in vitro (cultured dorsal spinal neurons of chick embryos) and in vivo (developing chick spinal commissural axons and rat callosal axons) findings demonstrate that knockdown of Kv3.4 by a specific shRNA impedes axon initiation, elongation, pathfinding, and fasciculation. In cultured dorsal spinal neurons, blockade of Kv3.4 by blood depressing substance II suppresses axon growth via an increase in the amplitude and frequency of Ca²⁺ influx through T-type and L-type Ca²⁺ channels. Electrophysiological results show that Kv3.4, the major Kv channel in the axonal growth cones of embryonic dorsal spinal neurons, is activated at more hyperpolarized potentials and inactivated more slowly than it is in postnatal and adult neurons. The opening of Kv3.4 channels effectively reduces growth cone membrane excitability, thereby limiting excessive Ca²⁺ influx at subthreshold potentials or during Ca²⁺-dependent action potentials. Furthermore, excessive Ca²⁺ influx induced by an optogenetic approach also inhibits axon growth. Our findings suggest that Kv3.4 reduces growth cone membrane excitability and maintains [Ca²⁺]_i at an optimal concentration for normal axon growth.SIGNIFICANCE STATEMENT Accumulating evidence supports the idea that impairments in axon growth contribute to many clinical disorders, such as autism spectrum disorders, corpus callosum agenesis, Joubert syndrome, Kallmann syndrome, and horizontal gaze palsy with progressive scoliosis. Membrane excitability in the growth cone, which is mainly controlled by voltage-gated Ca²⁺ (Cav) and K⁺ (Kv) channels, modulates axon growth. The role of Cav channels during axon growth is well understood, but it is unclear whether Kv channels control axon outgrowth by regulating Ca²⁺ influx. This report shows that Kv3.4, which is transiently expressed in the axonal growth cones of many types of embryonic neurons, acts to reduce excessive Ca²⁺ influx through Cav channels and thus permits normal axon outgrowth.
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PMID:K⁺ Channel Kv3.4 Is Essential for Axon Growth by Limiting the Influx of Ca²⁺ into Growth Cones. 2832 Aug 40

In the nervous system, Kirrel3 is involved in neuronal migration, axonal fasciculation, and synapse formation. Recently, genetic links have been reported between mutations in the KIRREL3 gene and increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability. To elucidate the causal relationship between KIRREL3 deficiency and behavioural abnormalities relevant to neurodevelopmental disorders, we generated global Kirrel3-knockout (Kirrel3^-/-) mice and investigated the detailed behavioural phenotypes. In the three-chambered social approach test, Kirrel3^-/- mice displayed a significant preference for a mouse over a non-social object but no significant preference for a stranger mouse over a familiar mouse. Ultrasonic communications, including pup-to-mother calls, male-female courtship vocalisation and resident responses to intruder, were significantly impaired in Kirrel3^-/- mice. Significant increases in locomotor activity and repetitive rearing were also observed in Kirrel3^-/- mice. Furthermore, the performance of Kirrel3^-/- mice in the rotarod test was significantly better than that of wild-type mice. In the acoustic startle test, Kirrel3^-/- mice were significantly hypersensitive to acoustic stimuli. Anxiety-related behaviours and spatial or fear memory acquisition were normal in Kirrel3^-/- mice. These findings suggest that Kirrel3^-/- mice exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviours, and sensory abnormalities, as well as hyperactivity.
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PMID:Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice. 2936 45

Neuron-Glia related cell adhesion molecule (NrCAM) is a candidate autism risk factor that promotes axon guidance through cytoskeletal linkages in developing brain but its role in limbic circuitry has not been investigated. In situ hybridization (ISH) and immunofluorescence staining showed that NrCAM is expressed in the developing amygdalar pathway of mouse embryos during outgrowth of projections in the stria terminalis, a major limbic tract that interconnects the central amygdala (CeA) with key targets in the bed nucleus of the stria terminalis (BNST). Analysis of fiber tracts in NrCAM mutant mice by Neurofilament protein immunohistochemistry showed pronounced defasciculation and misprojection of fibers in the ST. The defasciculation phenotype may result from impairment in NrCAM homophilic inter-axonal adhesion or axon repulsion from the secreted ligand Semaphorin 3F, which is expressed in limbic areas in proximity to the ST. Behavioral testing indicated that NrCAM null mice were impaired in context-dependent fear conditioning, in accord with altered amygdala-BNST connectivity, but displayed normal cued (tone-shock) conditioning. Results are consistent with the novel finding that NrCAM mediates fasciculation of axon fibers in the ST important for proper amygdalar-BNST circuitry and response to contextual fear conditioning.
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PMID:Expression and Function of Neuron-Glia-Related Cell Adhesion Molecule (NrCAM) in the Amygdalar Pathway. 3076 72