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Neighboring cells help neurons establish connections with one another

luan diniz / ufrjCreating networks: a protein secreted by astrocytes…luan diniz / ufrj

Long considered but secondary agents in the workings of the brain, glial cells only came to the fore over the last few years as research began to show their importance in the development, regeneration and structuring of the nervous system. Almost half of the brain’s cells are glia – the others are neurons – and recent studies have associated their malfunctioning with neurodegenerative diseases.  Researchers at the Federal University of Rio de Janeiro (UFRJ) have now discovered yet another important function of the glial cell. The biology research team of Flávia Alcantara Gomes found that astrocytes, the most common of the glial cells, control the connections (synapses) between neurons, the cells that transmit and store information in the brain.

“Without the glial cells, most of the synapses wouldn’t work efficiently,” says Gomes. In an article in the October 10, 2012 issue of the Journal of Biological Chemistry, Gomes and her colleagues demonstrate that a protein produced in abundance by the astrocytes– the transforming growth factor ß1 (TGF-ß1) – regulates the formation of synapses in mice and humans. For Gomes, the discovery presents new perspectives to better understand the role of glia in the development of neurological disturbances and the aging process. There is evidence that during the initial stages of some diseases and of aging, neurons, before they begin to die out, start to detach from one another.

The role of astrocytes in the formation of synapses has been suspected for some time. Approximately 10 years ago, Ben Barres, Frank Pfrieger and their colleagues at California’s Stanford University reported that neurons in laboratory mice generated more synapses when in the presence of astrocytes. The researchers went on to identify certain synapse-forming molecules secreted by these astrocytes. These molecules, however, merely stimulate the formation of the chemical cleft or the structure whereby neurons pass signals on to other cells, and where neurotransmission might not have functioned properly.

... induces the formation of synapses, the colored specks on the neurons

LUAN DINIZ / UFRJ… induces the formation of synapses, the colored specks on the neuronsLUAN DINIZ / UFRJ

The UFRJ team showed that the TGF-ß1 is able to do both things: induce the formation of these structures and of functionally active synapses. “We take two paths to the same conclusion,” Gomes explains. “One is a biochemical study using an in vitro model, and the other is an analysis to identify the electric currents typical of synapses.”

As the nervous system develops during its embryonic stage, the glial cells of the cerebral cortex function as stem cells. In adults, these glial cells of the nervous system can create neural cells as well as astrocytes. UFRJ researchers had already discovered that the TGF-ß1 induced the differentiation of progenitor stem cells in astrocytes, but not in neurons. The current research study has determined that the TGF-ß1 generated by the astrocytes plays a new role. Neurons grown in cultures with this protein generate at least three times more synapses than those grown in the media of normal cultures. The same occurs when the TGF-ß1 is injected directly into the cortices of live animals.

The team demonstrated that the role of the TGF-ß1 in forming synapses in the cerebral cortex is really an indirect one. The TGF-ß1 activates production of the D-serine amino acid (a compound made up of proteins), which is secreted by the neuron and then adheres to the neurotransmitter glutamine (see infographic).  Together, D-serine and glutamate activate the production of synapses in the neuron. The more D-serine there is present, the greater the number of synapses.

Now in humans
“The great merit of this research is, first of all, to show how astrocytes work biochemically to form the synapse and, second, to demonstrate this with cells derived from human tissue,” says neuroscientist Luiz Roberto Giorgetti de Britto of the University of São Paulo (USP). This is because, up to now, studies that examine the complex relationship between neurons and astrocytes have been carried out only in mice, not humans.

In the case of the human tissue trial, the team extracted astrocytes from the discarded brain tissue of epileptic patients who had undergone surgery at the UFRJ University Hospital. “As the human brain is more complex and difficult to work with, we have no standard procedures in place,” explains Gomes. The results were similar, demonstrating that, biochemically, the human cells behave just like the astrocytes of mice.

044-045_sinapse_204“Our work is the result of a multidisciplinary scientific collaboration among diverse basic research and clinical research teams,” says Gomes. On this note, the team is currently studying whether astrocytes from animal models or Alzheimer’s disease or from patients with epilepsy has the potential to induce the formation of synapses.     In parallel, the team plans a similar test with astrocytes from patients with schizophrenia.

“Cognitive ability in humans is associated with the complex of synaptic connections,” says Gomes. She then adds, “It follows that dysfunctions in processing information in the brain can lead to serious neurological disorders. Understanding the mechanism by which synapses are formed and regulated is a key step to understanding the brain and developing therapies to repair the nervous system.”

Scientific article
DINIZ, L.P. et al. Astrocyte-induced synaptogenesis is mediated by transforming growth factor beta signaling through modulation of D-serine levels in cerebral cortex neurons. Journal of Biological Chemistry. v. 287 (49), p. 41.432-45. 30 November 2012.