黑料吃瓜资源

Cold Spring Harbor, NY — Scientists at 黑料吃瓜资源 (CSHL) have solved part of a puzzle concerning the relationship between changes in the strength of synapses—the tiny gaps across which nerve cells in the brain communicate—and dysfunctions in neural circuits that have been linked with drug addiction, mental retardation and other cognitive disorders.

A team led by CSHL Professor Linda Van Aelst has pieced together essential steps in a signaling cascade within excitatory nerve cells that explains a key phenomenon called long-term depression, or LTD.聽The 鈥渄epression鈥� in question has nothing to do with the human illness with that name.聽Rather, it refers to a tamping-down of the strength of individual synapses—what scientists call synaptic plasticity.

The mechanism behind LTD is called endocytosis.聽It involves a retraction of receptors where neurotransmitters can 鈥渄ock.鈥澛燰an Aelst and colleagues have demonstrated how LTD works following activation of a class of receptors called group I metabotrobic glutamate receptors, or mGluRs.

It was known that long-term depression mediated by mGluRs depended in part on the rapid synthesis of specific proteins. Yet the identity of these proteins had largely remained a mystery.聽The CSHL scientists have now shown that locally rapid production of a protein called oligophrenin 1 (OPHN1) follows activation of group I mGluRs.聽OPHN1 in turn was shown to mediate LTD in hippocampal nerve cells, by interacting with yet another protein called EndophilinA2/3.

The result of this cascade of intracellular signals was dramatic: persistent removal of AMPA-type receptors at the excitatory synapse, and the onset of LTD.聽When rapid production of OPHN1 was blocked, mGluR-dependent LTD did not occur. These findings appear online today ahead of print in the journal Neuron.

Van Aelst explained the significance of the finding.聽鈥淥PHN1 has two important functions that we know about.聽One is early in development, after synapses have appeared in the emerging nervous system.聽In this phase, OPHN1 in concert with other factors stabilizes receptors at synapses, and thus is essential in maintaining the structure of these essential features of neural circuitry.

鈥淥ur new findings show another vital role for OPHN1, later in development and into maturity. We assume that in response to behavioral stimuli—we aren鈥檛 yet sure what kind—mGluRs are activated, setting off the series of steps that we identified: rapid upregulation of OPHN1, which binds to EndophilinA2/3, which in turn mediates the long-term removal of AMPA receptors.鈥�

OPHN1 is known to be associated with X-linked mental retardation and with other cognitive and behavioral deficits.聽The team hypothesizes that OPHN1-related changes in plasticity such as those described in their new work may be causally related to such pathology.聽They are investigating this possibility in their current work.

Written by: Communications Department | [email protected] | 516-367-8455

Funding

This work was supported by grants from the National Institue of Mental Health and NAAR.

Citation

鈥淩apid Synthesis of the X-linked Mental Retardation Protein OPHN1 Mediates mGluR-Dependent LTD through Interaction with the Endocytic Machinery鈥� appears online ahead of print October 19 in Neuron. The authors are: Nael Nadif Kasri, Akiko Nakano-Kobayashi and Linda Van Aelst.聽The paper can be accessed online at: http://www.cell.com/neuron