We are examining changes in neurotransmitter receptors following spinal cord injury.
For example, we find that the 5-HT2C receptor undergoes post trancriptional editing that leads to an isoform that is spontaneously active without serotonin (constitutively active receptors). Thus, this receptor recovers from loss of brain-derived serotonin, and ultimately contributes to recovery of motor function.
A prerequisite for normal movement is that motoneurons in the spinal cord are sufficiently excitable to be able to produce sustained muscle contractions in response to command signals from the brain. Motoneuron excitability is facilitated by neurochemicals like serotonin that come from the brainstem. Spinal cord injury causes loss of brainstem derived serotonin, which in turn leads to dramatically decreased motoneuron excitability and muscle weakness. Yet in the weeks after injury, motoneurons undergo a remarkable recovery, becoming very excitable. While this aids in the recovery of residual motor function, it also leads to the development of debilitating muscle spasms because the motoneurons are not under normal descending inhibitory control. We recently found that this recovery of motoneuron excitability and development of spasms involves monoamine receptors that somehow become activated despite the loss of most monoamines. We have found that this occurs because some monoamine receptors become constitutively active – spontaneously entering their active state without the binding of monoamines. This ultimately contributes to recovery of motoneuron functions such as walking. However, other receptors remain quiet after injury and the loss of function of these receptors leads to exaggerated reflex responses and the overall spasticity syndrome seen with injury. We have found that both walking and spasms can be controlled by modulating these monoamine receptors with new drugs that we have identified. This will translate into new treatments for humans after spinal cord injury, especially as some of these drugs are currently available therapeutics for other conditions (cyproheptadine).