These investigators will study a mouse model to determine whether immune microglial cells, which reside in the brain and spinal cord, produce inflammatory signals in response to a virus that ultimately leads to the death of motor neurons controlling movement. A similar disease in humans is the devastating and fatal Amyotrophic Lateral Sclerosis (ALS), often referred to as Lou Gehrig's disease. The research findings may demonstrate how anti-inflammatory agents can block initiation of this chain of events, thus preventing motor neuron disease.
As in the brain, microglial cells are the only resident immune cells in the spinal cord. Scientists have not yet determined how effectively microglial cells attack invaders in the brain or the spinal cord, which together comprise the central nervous system (CNS). Additionally, scientists suspect that microglial cells inflict harm to other CNS cells under certain circumstances. In the case of ALS, the researchers suggest, microglial cells become activated and produce inflammatory mediators. These mediators then precipitate a chain of events which results in destruction of the neurons that control movement (the "motor" neurons).
Many neurons communicate with one another using an excitatory neurotransmitter called glutamate. As glutamate is transmitted at the junction (synapse) from one nerve cell to another, excess glutamate spills out into the space surrounding the synapse. The spilled glutamate is ordinarily picked up by cells called astrocytes. This prevents high concentrations of glutamate from forming around the motor neuron synapse. If astrocytes fail to clear this excess glutamate, however, the neurotransmitter will overexcite motor neurons and cause them figuratively to fire to death. Literally, the excess glutamate causes the cells to degenerate and die.
This is what happens in the motor neuron disease ALS, the researchers hypothesize. Specifically, the researchers suggest, astrocytes fail to pick up the spilled glutamate because their receptors for glutamate become damaged and dysfunctional. These receptors are called "glutamate transporters." How these transporters are damaged has been a mystery.
Recent studies may provide a clue. They suggest that specific types of inflammation that are activated by microglial cells within the CNS precede the loss of glutamate transporters' function and their ability to clear away excess glutamate. Attempts to study this relationship between a preceding immune inflammatory response and subsequent astrocyte receptor failure have been difficult. The difficulty arises because the course of the animal model of ALS is exceedingly slow. The Hopkins researchers have circumvented this problem by developing an animal model disease that is similar to ALS but progresses much more rapidly. The disease is produced by a virus known as Sinabis. It causes severe ALS-like hind limb paralysis and progressive motor neuron destruction in the spinal cord in just eight to ten days.
The investigators will use this viral infection animal model to test their hypothesis that the virus activates immune microglial cells in the spinal cord to produce an inflammatory response. This inflammation interferes with glutamate transporters on astrocytes, preventing the astrocytes from taking up the excess glutamate that accumulates in the synaptic junction between two motor neurons. The resultant excessive concentrations of glutamate cause motor neurons to fire endlessly and eventually die.
If the researchers' hypothesis is correct, the results could spur the development of experimental anti-inflammatory therapies to stop this chain of events at its source: the initiation of inflammation by microglial cells.
