Novel Bar-Code Technique Used to Identify Critical Brain Cell Types

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Bar code
Two molecular markers, indicated by the red and green fluorescence, are found together only in synaptic Schwann cells. Together they offer a "bar code" that identifies Schwann cells, an important subtype of glia. [Valdez Lab / Center for Translational Neuroscience / Brown University]

Despite the significance of glial cells for the proper formation, maintenance, and repair of synapses throughout the nervous system, the inability to distinguish specific glial cells at synapses from the diverse overall population of glial cells has been a major challenge in promoting and restoring the normal function of the nervous system following injuries, diseases. and in old age.

Now, a new discovery described in eLifeSpecific labeling of synaptic schwann cells reveals unique cellular and molecular features” may change that.

A team led by Gregorio Valdez, PhD, an associate professor of molecular biology, cell biology, and biochemistry at Brown University, has identified important molecules to study and to manipulate the specific glial cells integral to synapses.

“Perisynaptic Schwann cells (PSCs) are specialized, non-myelinating, synaptic glia of the neuromuscular junction (NMJ), that participate in synapse development, function, maintenance, and repair. The study of PSCs has relied on an anatomy-based approach, as the identities of cell-specific PSC molecular markers have remained elusive. This limited approach has precluded our ability to isolate and genetically manipulate PSCs in a cell specific manner,” write the investigators.

“We have identified neuron-glia antigen 2 (NG2) as a unique molecular marker of S100β+ PSCs in skeletal muscle. NG2 is expressed in Schwann cells already associated with the NMJ, indicating that it is a marker of differentiated PSCs. Using a newly generated transgenic mouse in which PSCs are specifically labeled, we show that PSCs have a unique molecular signature that includes genes known to play critical roles in PSCs and synapses.”

“These findings will serve as a springboard for revealing drivers of PSC differentiation and function.”

“This discovery will serve as a springboard to addressing fundamental questions and developing assays to speed the discovery of therapeutics intended to preserve and restore the normal function of neuronal circuits,” said Valdez, who is affiliated with the new Center for Translational Neuroscience, established by the Carney Institute for Brain Science at Brown and the Brown Institute for Translational Science.

The study reveals that an important subtype of glia, known as Schwann cells and located at neuromuscular synapses, are the only cells in muscles expressing two specific molecules. These molecular markers provide a highly specific glial “bar code,” Valdez says, that identifies the vital cell subtype.

“What this means is that we can finally figure out how all three cellular constituents of the synapse—neurons, muscle and glia—talk to each,” Valdez continued. “We now have a unique and important tool for identifying this critical component of the synapse. This is essential for knowing when and where to target to ensure synapses function appropriately.”

Valdez says the novel bar code tool will pave the way for future studies, including on neuromuscular disease such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Scientists can use the molecular markers to probe the role of synaptic glia in neuromuscular synapse repair following injury, degeneration during normal aging and the progression of neuromuscular diseases.

He also anticipates that a similar approach will reveal the synaptic glial cells located at synapses between pairs of neurons in the brain.

“While our primary focus was the neuromuscular synapse, we also gathered initial evidence indicating that synaptic glia cells in the brain can be labeled and targeted using the same approach,” he said. “If true, this discovery could be of immense consequence for treating a myriad of brain conditions, including those involving cognitive decline due to normal aging and Alzheimer’s Disease.”

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