Damage to Nerve Synapses in MS Mouse Model Found to Be Unrelated to Myelin Destruction

Researchers found that nerve cell connections in the brain, called synapses, were damaged in a mouse model of multiple sclerosis (MS) through a process wholly unrelated to myelin destruction. As the damaged mice synapses studied were in regions crucial for memory processing, finding ways of protecting these neurons would be a crucial step toward developing a treatment that preserves cognitive function in MS patients.

The study — published in the Journal of Neuroscience under the title “Platelet-Activating Factor Receptors Mediate Excitatory Postsynaptic Hippocampal Injury in Experimental Autoimmune Encephalomyelitis“ — gives scientists entirely new insights into processes of nerve damage affecting MS patients.

In previous research, scientists observed that damage to the brain’s gray matter — areas holding densely packed unmyelinated nerve cell bodies — occur without correlation to myelin destruction. In MS, damage to these neurons occur in areas that are important for cognition, thereby contributing to disability.

Scientists, however, know little about the mechanisms behind damage to these nerve cells. Because of this, attempts to develop therapies that might protect the neurons from damage so as to slow or stop the disease’s progressive disability are still in their infancy.

The team, led by Matthew Bellizzi and Harris Gelbard at the University of Rochester Medical Center, studied mice with experimental autoimmune encephalopathy (EAE), used to model MS. They focused on the hippocampus, a brain region crucial for the processing of memories, particularly spatial memory, and the process of consolidating short-term memories into long-term ones.

When researchers compared the density of synapses in the EAE mice to normal mice, they saw that the MS-like mice had a 28 percent reduction in synaptic density, despite intact myelin. The team also noted that activated microglial cells were present at the same sites where scientists found synaptic debris. Microglia are the brain’s main type of immune cell, and when activated they are known to produce substances that can be toxic to neurons.

To determine if the presence of microglia contributed to the damage, researchers then cultured neurons from the hippocampus in the lab. When they added activated microglia, they noted that the neurons became more vulnerable to damage. They also observed that this increased sensitivity seemed to be mediated by a factor called platelet-­activating factor receptor (PAFR).

To confirm the role of PAFR, the team then blocked PAFR in the EAE mice using the experimental molecule BN52021. When PAFR was blocked, synapses were preserved, but other signs of disease remained. More research is now needed to find ways to protect these neurons in humans with MS.

According to a news release from the National MS Society, which partly funded the study, the Rochester team next plans to search for potential drug candidates based on these findings.