Identification of a new target for the treatment of spinal cord injuries

Summary: Researchers have discovered a drug target that could prevent autonomic dysfunction after spinal cord injury. Research has found that microglial cells control abnormal nerve growth and autonomic reflexes.

By depleting microglia in a mouse model, researchers avoided potentially fatal complications. This discovery could lead to new treatments for spinal cord injuries and other neurological disorders.

Highlights:

1. Microglial cells control abnormal nerve growth and autonomic reflexes after injury.
2. Depletion of microglia in mice prevented autonomic complications after spinal cord injury.
3. This discovery could lead to new treatments for dysautonomia in various neurological conditions.

Source: Ohio State University

In response to stressful or dangerous stimuli, nerve cells in the spinal cord activate involuntary autonomic reflexes, often called “fight or flight” responses.

These protective responses cause changes in blood pressure and the release of stress hormones into the bloodstream. Normally, these responses are short-lived and well-controlled, but this changes after traumatic spinal cord injury.

A very first study published in the journal Scientific translational research identifies a druggable cellular target that, if controlled properly, could prevent or alleviate autonomic dysfunction and improve the quality of life of people with spinal cord injuries.

“We found that exaggerated and life-threatening autonomic reflexes after spinal cord injury are associated with abnormal growth and rewiring of nerve fibers in the spinal cord. A specific type of cell, called microglia, controls this abnormal growth and rewiring,” said corresponding author Phillip Popovich, PhD, professor and chair of the Department of Neuroscience at The Ohio State University Wexner Medical Center and College of Medicine. .

“By using experimental tools to deplete microglia, we found that it is possible to prevent abnormal nerve growth and prevent autonomic complications after spinal cord injury,” said Popovich, who is also executive director of the Belford Center for Spinal Cord Injury at Ohio State.

This research used a mouse model of spinal cord injury. However, abnormal, potentially fatal autonomic reflexes also occur in other animals and in people with spinal cord injuries, said Popovich, who is also a member of the State Institute of Behavioral Medicine. Ohio.

Autonomic dysfunction or “dysautonomia” is a major problem for people living with spinal cord injuries.

In people and animals with spinal cord injuries, normally harmless stimuli, such as a full bladder, can weaken the body's immune system and cause uncontrolled changes in blood pressure.

This leads to life-threatening complications, including heart attack, stroke, metabolic disease, and serious infections, such as pneumonia.

There is currently no treatment to prevent dysautonomia.

“We consider this to be a major finding,” said first author Faith Brennan, PhD, who began this work at Ohio State and is now a neuroscience researcher at Queen's University in Kingston. in Ontario. “Although this is a well-known consequence of spinal cord injury, research has primarily focused on how the injury affects the neurons that control autonomic function. »

Improving autonomic function is a top priority for people living with spinal cord injury. Limiting the effects of dysautonomia after spinal cord injury would significantly increase quality of life and life expectancy, Popovich said.

The next steps in this research will focus on identifying the specific neuron-derived signals that control microglia, causing them to remodel spinal autonomic circuits.

“Identifying these mechanisms could lead to the design of new, highly specific treatments to treat dysautonomia after spinal cord injury.” It could also help in other neurological complications where dysautonomia develops, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, stroke and head trauma,” Popovich said.

Funding: This research was supported by the National Institutes of Health, the Ray W. Poppleton Endowment, the Craig H. Neilsen Foundation, and the Wings for Life Spinal Research Foundation.

About this spinal cord injury research news

Author: Eileen Schahill
Source: Ohio State University
Contact: Eileen Scahill – Ohio State University
Picture: Image is credited to Neuroscience News

Original research: Closed access.
“Microglia promote maladaptive plasticity in autonomic circuits after spinal cord injury in mice” by Phillip Popovich et al. Scientific translational medicine

Abstract

Microglia promote maladaptive plasticity in autonomic circuits after spinal cord injury in mice

Robust structural remodeling and synaptic plasticity occur in spinal autonomic circuits after severe spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli cause uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology.

How hyperexcitable sympathetic circuits form is unknown, but local signals from neighboring glial cells likely help shape these maladaptive neural networks.

Here, we used a mouse model of SCI to show that microglia surround active glutamatergic interneurons and subsequently coordinate multi-segmental excitatory synaptogenesis and the expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions.

Depletion of microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity of autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression.

Forced microglia turnover in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity.

Additional data show that microglia-dependent autonomous plasticity required the expression of trigger receptor expressed on myeloid cells 2 (Trem2) and α2δ-1-dependent synaptogenesis. These data suggest that microglia are the main effectors of autonomic neuroplasticity and dysautonomia after SCI in mice.

Manipulation of microglia may be a strategy to limit autonomic complications after spinal cord injury or other forms of neurological disease.