There are new clues about malfunctions in brain cells that contribute to intellectual disability and possibly other developmental brain disorders.
Professor Linda Van Aelst of Cold Spring Harbor Laboratory (CSHL) has been scrutinizing how the normal version of a protein called OPHN1 helps enable excitatory nerve transmission in the brain, particularly at nerve-cell docking ports containing AMPA receptors (AMPARs).
False color image of a mouse hippocampal neuron (cell body is at lower right) with branchlike dendrites that provide surfaces at which projections from other neurons can connect, by forming synapses. Van Aelst and colleagues have shown that when the OPHN1 protein is mutated, interfering with its ability to interact with another protein called Homer1b/c, AMPA receptors don't recycle to the surface at synapses at the rate they normally do. This adversely impacts synaptic plasticity, the process by which neurons adjust the strength of their connections. Such pathology may play a role in X-linked mental retardation.
Credit: Van Aelst Laboratory, CSHL
Her team's new work, published June 24 in the Journal of Neuroscience, provides new mechanistic insight into how OPHN1 defects can lead to impairments in the maturation and adjustment of synaptic strength of AMPAR-expressing neurons, which are ubiquitous in the brain and respond to the excitatory neurotransmitter glutamate.
Mutations in a gene called oligophrenin-1 (OPHN1) – located on the X chromosome – have previously been linked to X-linked intellectual disability (also known as X-linked mental retardation), a condition that affects boys disproportionately and could account for as much as one-fifth of all intellectual disability among males.
Several different mutations in the OPHN1 gene have been identified to date, all of which perturb nerve cells' manufacture of OPHN1 protein. Previously, Van Aelst and colleagues demonstrated that OPHN1 has a vital role in synaptic plasticity, the process through which adjacent nerve cells adjust the strength of their connections. Cells in the brain are constantly adjusting connection strength as they respond to streams of stimuli.
The new discovery shows how OPHN1 is involved in the trafficking of AMPARs, an essential feature of plasticity in neurons. Neurons move receptors away from synapses into their interior and then back to the surface of synapses to control connection strength. At the synaptic surface, receptors provide an opportunity for the docking of neurotransmitters, in this case glutamate molecules. After a cell has fired, surface receptors are typically brought back into the interior, where they are recycled for future use.
When OPHN1 is misshapen or missing due to genetic mutation, the CSHL team demonstrated, it can no longer properly perform its role in receptor recycling, thus also impairing neurons' ability to maintain strong long-term connections with their neighbors, called long-term potentiation.
Van Aelst's new experiments explain how OPHN1 in complex with another protein called Homer1b/c should normally interact with an area called the endocytic zone (EZ) to provide a pool of AMPARs to be brought to the synapse at a location called the post-synaptic density (PSD). When OPHN1 is mutated, the pool does not form and receptors needed for strengthening synapses are not available. Long-term potentiation is impaired.
"This suggests a previously unknown way in which genetic defects in OPHN1 can lead to dysfunctions in the glutamate system," says Dr. Van Aelst. "Our earlier studies had already shown that OPHN1 is essential in stabilizing AMPA receptors at the synapse. Together, these two essential roles suggest how defective OPHN1 protein may contribute to pathology that underlies X-linked intellectual disability."
The research described in this release was supported by National Institutes of Health Grants RO1-MH082808 and RO1-NS082266.
"The X-linked Mental Retardation Protein OPHN1 Interacts with Homer1b/c to Control Spine Endocytic Zone Positioning and Expression of Synaptic Potentiation" appears online ahead of print in
The Journal of Neuroscience on June 25, 2014. The authors are:
Akiko Nakano-Kobayashi, Yilin Tai, Nael Nadif Kasri, and Linda Van Aelst. The paper can be obtained at: http://www.jneurosci.org
About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for the impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 600 researchers and technicians strong and its Meetings & Courses program hosts more than 12,000 scientists from around the world each year to its Long Island campus and its China center. For more information, visit http://www.cshl.edu
Peter Tarr | Eurek Alert!
Two decades of training students and experts in tracking infectious disease
27.11.2015 | Hochschule für Angewandte Wissenschaften Hamburg
Increased carbon dioxide enhances plankton growth, opposite of what was expected
27.11.2015 | Bigelow Laboratory for Ocean Sciences
Planet Earth experienced a global climate shift in the late 1980s on an unprecedented scale, fuelled by anthropogenic warming and a volcanic eruption, according to new research published this week.
Scientists say that a major step change, or ‘regime shift’, in the Earth’s biophysical systems, from the upper atmosphere to the depths of the ocean and from...
The Fraunhofer Institute for Solar Energy Systems ISE has installed 70 photovoltaic modules on the outer façade of one of its lab buildings. The modules were...
Nerve cells cover their high energy demand with glucose and lactate. Scientists of the University of Zurich now provide new support for this. They show for the first time in the intact mouse brain evidence for an exchange of lactate between different brain cells. With this study they were able to confirm a 20-year old hypothesis.
In comparison to other organs, the human brain has the highest energy requirements. The supply of energy for nerve cells and the particular role of lactic acid...
In laser material processing, the simulation of processes has made great strides over the past few years. Today, the software can predict relatively well what will happen on the workpiece. Unfortunately, it is also highly complex and requires a lot of computing time. Thanks to clever simplification, experts from Fraunhofer ILT are now able to offer the first-ever simulation software that calculates processes in real time and also runs on tablet computers and smartphones. The fast software enables users to do without expensive experiments and to find optimum process parameters even more effectively.
Before now, the reliable simulation of laser processes was a job for experts. Armed with sophisticated software packages and after many hours on computer...
Researchers at Heidelberg University have devised a new way to study the phenomenon of magnetism. Using ultracold atoms at near absolute zero, they prepared a...
25.11.2015 | Event News
17.11.2015 | Event News
21.10.2015 | Event News
27.11.2015 | Life Sciences
27.11.2015 | Physics and Astronomy
27.11.2015 | Earth Sciences