Posts tagged neurexin
Articles and news from the latest research reports.
Protein Family Linked to Autism Suppresses the Development of Inhibitory Synapses
Synapse development is promoted by a variety of cell adhesion molecules that connect neurons and organize synaptic proteins. Many of these adhesion molecules are linked to neurodevelopmental disorders; mutations in neuroligin and neurexin proteins, for example, are associated with autism and schizophrenia. According to a study in The Journal of Cell Biology, another family of proteins linked to these disorders regulates the function of neuroligins and neurexins in order to suppress the development of inhibitory synapses.
Like neurexins and neuroligins, the neuronal proteins MDGA1 and MDGA2 have been linked to autism and schizophrenia, but their function in neurodevelopment was unknown. Both MDGA proteins localize to the plasma membrane, and their extracellular domains are similar to those of cell adhesion molecules. On the other hand, postsynaptic neuroligin proteins are known to help synapses form by associating with neurexins on presynaptic membranes. Neuroligin-2 specifically boosts the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses.
Ann Marie Craig and colleagues from the University of British Columbia investigated the function of MDGAs using co-culture assays, in which postsynaptic proteins like neuroligin-1 or -2 are expressed in non-neuronal cells and then tested for their ability to induce presynaptic differentiation in neighboring neurons. MDGA1 didn’t promote synapse formation in these assays. Instead, it inhibited the ability of neuroligin-2 to promote synapse development. The researchers found that MDGA1’s extracellular domains bound to neuroligin-2, blocking its association with neurexin. The same domains were sufficient to inhibit neuroligin-2’s synapse-promoting activity. In contrast, MDGA1 didn’t show high affinity binding to, or inhibit the function of, neuroligin-1. This suggested that, by inhibiting neuroligin-2, MDGA1 might specifically suppress the development of inhibitory synapses, so Craig and colleagues investigated MDGA1 function in cultured hippocampal neurons.
“Overexpressing MDGA1 in neurons reduced the density of inhibitory synapses without affecting excitatory synapses,” Craig says. Knocking down MDGA1, on the other hand, increased inhibitory synapse development but had no effect on excitatory synapses.
“I can’t think of any other proteins that specifically suppress inhibitory synapse formation,” says Craig. Indeed, very few proteins in general have been identified as negative regulators of synapse development, compared to the many proteins that are known to promote synaptogenesis. The results suggest that function-altering mutations in the MDGA proteins may disrupt the balance of excitatory and inhibitory synapses in the brain, potentially explaining the development of autism and other neurodevelopmental disorders.
“This puts MDGAs in the same pathway as neurexins and neuroligins and strengthens the evidence for the involvement of synaptic organizing proteins in autism and schizophrenia,” Craig explains. As well as investigating the function of MDGA2, the researchers want to explore the therapeutic potential of MDGA1 inhibitors, not only against autism and schizophrenia but also for the treatment of epilepsy, in which excitatory and inhibitory synapses are also imbalanced.
(Source)
Does the Brain Become Unglued in Autism?
A new study published in Biological Psychiatry suggests that autism is associated with reductions in the level of cellular adhesion molecules in the blood, where they play a role in immune function.
Cell adhesion molecules are the glue that binds cells together in the body. Deficits in adhesion molecules would be expected to compromise processes at the interfaces between cells, influencing tissue integrity and cell-to-cell signaling. In the brain, deficits in adhesion molecules could compromise brain development and communication between nerve cells.
Over the years, deficits in neural cell adhesion molecules have been implicated in schizophrenia and other psychiatric disorders. One adhesion molecule, neurexin, is strongly implicated in the heritable risk for autism.
Cell adhesion molecules also play a crucial role in regulating immune cell access to the central nervous system. Prior research provided evidence of immune system dysfunction in individuals diagnosed with autism spectrum disorder (ASD). This led scientists from the University of California, Davis to examine whether adhesion molecules are altered in children with ASD.
"For the first time, we show that levels of soluble sPECAM-1 and sP-selectin, two molecules that mediate leukocyte migration, are significantly decreased in young children with ASD compared with typically developing controls of the same age," explained the authors. "This finding is consistent with previous reports of decreased levels of both sPECAM-1 and sP-selectin in adults with high-functioning autism."
They also found that repetitive behavior scores and sPECAM-1 levels were associated in children with ASD. Repetitive, stereotyped behaviors are a typical feature of ASD and these data suggest a potential relationship between molecule levels and the severity of repetitive behaviors.
Finally, they also discovered that head circumference was associated with increased sPECAM-1 levels in the typically developing children, but not in the children with ASD. This indicates that perhaps sPECAM-1 plays a role in normal brain growth, as larger head circumference is a known feature of individuals with autism.
(Image courtesy of Cord Blood Registry)