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

1. Autism is a severe neurodevelopmental disorder with potential genetic and environmental etiologies. Recent genetic linkage reports and biochemical analysis of postmortem autistic cerebellum point to Reelin, an important secretory extracellular protein, as being involved in the pathology of autism. 2. We hypothesized that blood levels of Reelin and its isoforms would be altered in autistic twins, and their first degree relatives versus normal controls. 3. We measured blood levels of unprocessed Reelin (410 kDa) and its proteolytic cleavage products (Reelins 330 and 180 kDa) as well as albumin and ceruloplasmin in 28 autistic individuals, their parents (13 fathers, 13 mothers), 6 normal siblings, and 8 normal controls using SDS-PAGE and western blotting. 4. Results indicated significant reductions in 410 kDa Reelin species in autistic twins (-70%, p < 0.01), their fathers (-62%, p < 0.01), their mothers (-72%, p < 0.01), and their phenotypically normal siblings (-70%, p < 0.01) versus controls. Reelin 330 kDa values did not vary significantly from controls. Reelin 180 kDa values for parents (fathers -32% p < 0.05 vs. controls, mothers -34%) declined when compared to controls. In contrast autistic Reelin 180 kDa increased, albeit nonsignificantly versus controls. Albumin and ceruloplasmin values for autistics and their first degree relatives did not vary significantly from controls. There were no significant meaningful correlations between Reelin, albumin and ceruloplasmin levels, age, sex, ADI scores, or age of onset. 5. These results suggest that Reelin 410 deficiency may be a vulnerability factor in the pathology of autism.
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PMID:Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. 1236 96

The neurobiologic basis of autism is reviewed, with discussion of evidence from genetic, magnetic resonance imaging, neuropathology, and functional neuroimaging studies. Although autism is a behaviorally valid syndrome, it is remarkably heterogeneous and involves multiple developmental domains as well as a wide range of cognitive, language, and socioemotional functioning. Although multiple etiologies are implicated, recent advances have identified common themes in pathophysiology. Genetic factors play a primary role, based on evidence from family studies, identification of putative genes using genome-wide linkage analyses, and comorbidities with known genetic mutations. The RELN gene, which codes for an extracellular protein guiding neuronal migration, has been implicated in autism. Numerous neuropathologic changes have been described, including macroencephaly, acceleration and then deceleration in brain growth, increased neuronal packing and decreased cell size in the limbic system, and decreased Purkinje cell number in the cerebellum. Abnormalities in organization of the cortical minicolumn, representing the fundamental subunit of vertical cortical organization, may underlie the pathology of autism and result in altered thalamocortical connections, cortical disinhibition, and dysfunction of the arousal-modulating system of the brain. The role of acquired factors is speculative, with insufficient evidence to link the measles-mumps-rubella (MMR) vaccine with autism or to change immunization practices.
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PMID:The neurobiology of autism: new pieces of the puzzle. 1258 44

Recent studies have identified the leucine rich repeat protein LRRTM2 as a post-synaptic ligand of Neurexins. Neurexins also bind the post-synaptic adhesion molecules, Neuroligins. All three families of genes have been implicated in the etiologies of neurodevelopmental disorders, specifically autism spectrum disorders and schizophrenia. Does the binding promiscuity of Neurexins now suggest complex cooperativity or redundancy at the synapse? While recent studies in primary neuronal cultures and also systematic extracellular protein interaction screens suggest summative effects of these systems, we propose that studying these interactions in the developing zebrafish embryo or larvae may shed more light on their functions during synaptogenesis in vivo. These gene families have recently been extensively characterized in zebrafish, demonstrating high sequence conservation with the human genes. The simpler circuitry of the zebrafish, together with the characterization of the expression patterns down to single, identifiable neurons and the ability to knock-down or over-express multiple genes in a rapid way lend themselves to dissecting complex interaction pathways. Furthermore, the capability of performing high-throughput drug screens suggests that these small vertebrates may prove extremely useful in identifying pharmacological approaches to treating autism spectrum disorders.
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PMID:Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy. 2115 6

An increasing number of rare mutations linked to autism spectrum disorders have been reported in genes encoding for proteins involved in synapse formation and maintenance, such as the post-synaptic cell adhesion proteins neuroligins. Most of the autism-linked mutations in the neuroligin genes map on the extracellular protein domain. The autism-linked substitution R451C in Neuroligin3 (NLGN3) induces a local misfolding of the extracellular domain, causing defective trafficking and retention of the mutant protein in the endoplasmic reticulum (ER). The activation of the unfolded protein response (UPR), due to misfolded proteins accumulating in the ER, has been implicated in pathological and physiological conditions of the nervous system. It was previously shown that the over-expression of R451C NLGN3 in a cellular system leads to the activation of the UPR. Here, we have investigated whether this protective cellular response is detectable in the knock-in mouse model of autism endogenously expressing R451C NLGN3. Our data showed up-regulation of UPR markers uniquely in the cerebellum of the R451C mice compared to WT littermates, at both embryonic and adult stages, but not in other brain regions. Miniature excitatory currents in the Purkinje cells of the R451C mice showed higher frequency than in the WT, which was rescued inhibiting the PERK branch of UPR. Taken together, our data indicate that the R451C mutation in neuroligin3 elicits UPR in vivo, which appears to trigger alterations of synaptic function in the cerebellum of a mouse model expressing the R451C autism-linked mutation.
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PMID:UPR activation specifically modulates glutamate neurotransmission in the cerebellum of a mouse model of autism. 3020 12

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer's disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.
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PMID:Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. 3260 86