The decoupling of neurons could be a strategy for neuroprotection

A study indicates that the spread of cell death can be reduced through reversion of the coupling among nerve cells that is normally responsible for communication through electrical synapses

By Fábio de Castro

Agência FAPESP – In addition to the well-known chemical synapses – which allow for interactions among nerve cells and involve neurotransmitters and receptors – neurons also communicate with electrical synapses. In this type of synapse, ion currents move directly from one cell to another through channels known as “gap junctions,” producing neuron coupling.

A study conducted by Brazilian researchers shows that the decoupling of neurons could be a simple and effective neuroprotection strategy. This decoupling could interrupt the processes of cell death related to neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and epilepsy.

Professor Alexandre Kihara, coordinator of post-graduate studies in Neuroscience and Cognition at Universidade Federal do ABC (UFABC), led the study published in PLoS One. The study was funded by FAPESP under its Young Investigators in Emerging Centers Program.

In addition to Kihara, study participants included Vera Paschon and Guilherme Higa – both FAPESP fellows – along with professors Luiz Roberto Britto of the Department of Physiology and Biophysics at the Universidade de São Paulo’s Biomedical Sciences Institute (ICB-USP) and Rodrigo Resende of the Biochemistry Department at Universidade Federal de Minas Gerais (UFMG).

According to Kihara, although electrical synapses have historically been less thoroughly studied than their chemical counterparts, scientists currently recognize that electrical synapses have fundamental roles in diverse physiological and cognitive functions such as development, learning, memory and perception. Recent studies have also shown that the participation of gap junctions in neuron coupling is related to the spread of apoptosis or to cell death.

“In apoptosis, which is a common process in all neurodegenerative diseases, the neuron alters its internal programming to commit ‘suicide.’ As it were, if a neuron undergoing apoptosis is coupled with a healthy neuron – as this study shows – this coupling allows the passage of certain molecules that increase the probability that the healthy cell will undergo apoptosis as well,” explained Kihara in an interview with Agência FAPESP.

According to Kihara, however, scientists are still determining which molecules are involved in the spread of apoptosis through neuron coupling. In addition to traditional second messengers – such as IP3, an important calcium signaler – the UFABC group hypothesized that microRNAs (miRNAs) could be involved in the process.

“miRNAs negatively regulate translation and represent an additional layer of control between mRNA and protein. The proposal that miRNAs can traffic through gap junctions is considered very bold. Nevertheless, no one has managed to raise concrete arguments against this hypothesis, and we already have some evidence in favor of it,” said Kihara.

Coupling alone is not sufficient for molecular traffic to occur among cells. There must also be gradients – that is, one of the coupled neurons must have a greater concentration of molecules than the other. The researchers generated gradients by producing lesions with extremely fine needles on the retinas of roosters (Gallus gallus).

The lesions were sufficiently focused to produce cell death in a specific area of the tissue without affecting its surroundings, generating a gradient. The neuronal coupling was pharmacologically manipulated with several drugs. When the drugs decoupled the neurons, the researchers observed a reduction in the spread of cell death.

“The strategy was to produce an acute, localized lesion with the purpose of generating concentration gradients in the tissue to later biochemically decouple the neurons. This is why the double approach was utilized, combining in vivo retina lesions with explant retina lesions, an in vitro model that is more appropriate than traditional cell cultures,” explained Kihara.

Potential applications

The neuroprotection strategy utilizing different molecules that decouple neurons was also able to negatively regulate pro-apoptotic genes such as caspases. “The strategy proved to be so efficient that it was reproduced in vivo, resulting in reductions of the affected area and of neuronal death,” explained Kihara.

“We also showed that neurons undergoing apoptosis maintain the expression of connexins, which are the proteins responsible for forming gap conjunction channels, allowing for the occurrence of coupling. This is important because in this manner, we could eliminate the hypothesis that a neuron undergoing apoptosis stops expressing the proteins that form the coupling channels,” he said.

According to Kihara, future studies will investigate the hypothesis that miRNAs transit through gap junctions and participate in the process of spreading apoptosis among coupled cells.

The team investigating this hypothesis will be joined by Erica de Sousa, a graduate student at UFABC and author of a chapter on miRNAs in the book Calcium Signaling: Biochemistry and Cellular Physiology (Sinalização de Cálcio: Bioquímica e Fisiologia Celulares), released in early October at the 1st Brazilian Symposium on Biochemistry and Cellular Physiology at UFMG.

According to Kihara, the studies will also continue to explore the possibility of utilizing the decoupling of neurons as a neuroprotection strategy with potential applications in the treatment of neurodegenerative diseases.

“We will continue investigating how and when to do this in the most efficient manner, depending on the disease. We believe that a new door has been opened for neurodegeneration studies,” he said.

The article “Blocking of Connexin-Mediated Communication Promotes Neuroprotection during Acute Degeneration Induced by Mechanical Trauma” by Vera Paschon and others can be read at PLoS One: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045449.