A team of researchers working at McGill University has found that activation of microglia in the spinal cord following a nerve injury can lead to an increased sensitivity to pain. In their paper published in the journal Science, the group describes their study of nerve cells in injured mice and what it showed them about the possible source of some types of chronic back pain.

To learn more about the source of some types of chronic back pain, the researchers effectuated backbone nerve injuries in eight 12-week-old mice. They then collected projection neuron samples from them. Such nerve cells are known to transmit pain signals. Next, the researchers applied a stain to the projection neurons still left in the mice. Its purpose was to show whether an outer covering known as perineuronal net (PNN) was present. They found that, after injury, the volume of PNN on the projection neurons fell by 76.3% over three days. They also found that the stain had made its way to microglia—a type of immune cell.

To learn more about the role that microglia might be playing in the decrease in PNN, the researchers worked with a new group of mice. First, they divided them into two groups. One group had their microglia removed. Testing showed that those mice did not see a drop in PNN after injury, while the other group, which had served as a control, did.

The researchers then removed the PPN from the projection neurons in a new batch of mice and found that doing so resulted in hypersensitivity to heat (as seen by their facial expressions) and other instances of pain that occurred at random.

The researchers suggest their work shows that when microglia are activated by an injury they can degrade PPN, leading to chronic pain. They suggest other types of chronic pain may be due to the same process in other parts of the body, even those that are not part of the central nervous system. They note that more research will have to be done to find out if their findings apply to humans, and if so, whether therapies can be designed to prevent overreactions by microglia after injury.

When adult humans and animals severely injure their spinal cord, they become irreversibly paralyzed and are no longer able to move body parts controlled by the section of the spinal cord below their lesion. To counteract the damage done by the injury, doctors often use pharmacological agents or electrical stimulation tools.

While these treatments can have some positive effects, they only enable movements temporarily and do not restore full mobility in the long term. Interestingly, studies on rodents have showed that while severe spinal cord injuries cause permanent paralysis in adults, neonatal rodents with spinal cord lesions can recover much of their hindlimb mobility in adulthood, without receiving any targeted treatments.

Neuroscientists have been trying to understand the biological mechanisms underlying this renewed mobility for some years now. However, the reasons why the same type of injury experienced at different ages can have different long-term consequences on mobility remains unclear.

A team of researchers at VIB- Neuroelectrics Research Flanders (NERF) and Leuven Brain Institute have recently carried out a study investigating the mechanisms underlying the recovery of hindlimb mobility in neonatal rodents with spinal lesions. Their findings, published in Nature Neuroscience, suggest that this recovery could be regulated by the neurotransmitter phenotype switching of spinal excitatory interneurons.

In their experiments, the researchers subjected a series of wild mice to a complete spinal cord transection in the lower part of their thorax. The mice they operated on were either adults or five days old.

Subsequently, the researchers used high-speed cameras to observe and characterize the movements of the mice as they moved on a treadmill, comparing them to those of a control group of mice (i.e., mice with no spinal lesions). Finally, the researchers carried out a series of analyses to determine the biological and kinematic differences between the adult and post-natal mice with spinal cord injuries.

"We found that adult spinal cord injury prompts neurotransmitter switching of spatially defined excitatory interneurons to an inhibitory phenotype, promoting inhibition at synapses contacting motor neurons," Hannah Bertels, Guillem Vicente-Ortiz, Khadija El Kanbi, and Aya Takeoka wrote in their paper. "In contrast, neonatal spinal cord injury maintains the excitatory phenotype of glitamatergic interneurons and causes synaptic sprouting to facilitate excitation."

Essentially, the researchers' findings suggest that the recovery of hindlimb mobility in post-natal mice with spinal cord injuries is regulated by the switching of injury-specific neurotransmitter identities and the rearrangements of connectivity among excitatory interneurons. Excitatory interneurons are neurons that connect spinal motor and sensory neurons, which utilize the neurotransmitter glutamine.

Bertels and her colleagues then performed a series of further tests aimed at understanding their observations more in depth. The findings they collected offer valuable insight that could pave the way for new studies focusing on the consequences of severe spinal cord injuries.

"Genetic manipulation to mimic the inhibitory phenotype observed in excitatory interneurons after adult spinal cord injury abrogates autonomous locomotor functionality in neonatally injured mice," the researchers added in their paper. "In comparison, attenuating this inhibitory phenotype improves locomotor capacity after adult injury. Together, this data demonstrates that neurotransmitter phenotype of define excitatory interneurons steers locomotor recovery after spinal cord injury."

In the future, the findings gathered by this team of researchers could potentially help to identify more effective treatments and therapeutic interventions for re-gaining mobility after these injuries. These interventions could specifically target the regulation of interneurons, with the aim of regulating the balance of excitatory interneurons and promoting the recovery of mobility.

Internationally renowned neurobiologist Magdalena Götz is pursuing important leads in her quest to elucidate the causes of neurological diseases. Together with her team at Helmholtz Munich and Ludwig-Maximilians-Universität München, she has gained new insights into the human centrosome, whose malfunction is linked to many neurodevelopmental disorders.

The centrosome is the organelle responsible for the organization of the cytoskeleton during cell division, an essential function in organisms from yeast to humans. Until now, scientists assumed that the centrosome was very similar in all cells due to its general tasks. However, Götz and her team evaluated this notion in neurons and their developmental precursors, so-called neuronal stem cells. "There is so much we don't yet know about these cells, including how the centrosomes of neurons compare to those of neural stem cells and other cell types," Götz says. Their subsequent discoveries now fundamentally challenge the assumption that all centrosomes are created equal.

Centrosomes are not 'one type fits all'

In close collaboration with the Helmholtz Munich Proteomic Core Facility led by Stefanie Hauck, the researchers found that the composition of proteins in centrosomes differs profoundly depending on the cell type.

"We were surprised not only by the unexpected high degree of heterogeneity of the centrosomes, but also by the discovery of many unexpected proteins associated with them—for example, RNA-binding proteins and even proteins responsible for splicing (the processing of RNA), which normally takes place in the nucleus," Götz explains.

The location of centrosome-associated proteins is crucial for disease

The scientists discovered that a specific protein (the ubiquitously expressed splicing protein PRPF6) is enriched at the centrosome in neural stem cells, but not in neurons. A mutation of the protein found in patients with brain malformation periventricular heterotopia also leads to a similar phenotype in animal models.

Götz says that "this means that the location of a protein is crucial for a disease. With our centrosome analysis, we now have an important resource to test further associations with neuronal diseases. In particular, our research can explain for the first time why a protein that is present in all cells, after mutation, causes a phenotype only in the brain, but not in other organs. This will allow further insights into disease mechanisms—and thus get one step closer to their treatment."

The research was published in Science.