George Z. Mentis, PhD
- Associate Professor of Pathology and Cell Biology (in Neurology)
Developmental organization of motor neuronal circuitry
Spinal motor neurons serve as mediators of motor output from the central nervous system and in the context of locomotion, their activity is governed by a network of spinal neurons, known as the central pattern generator, which is responsible for the coordinated and patterned motor output.
Locomotion and the spinal network that generates the required patterns of muscle activity is an appealing system for studying how the nervous system produces complex behavior. In our laboratory, we have taken a developmental approach to the study of locomotion in the neonatal mouse – a system that offers several major experimental advantages: first, the isolated neonatal mouse spinal cord can generate locomotor-like activity in vitro, in response to stimulation of the brainstem, sensory fibers, as well as by application of pharmacological agents; and second, it is a genetically tractable system in which the identity and manipulation of spinal neurons via a set of molecular markers are employed to study their role in the formation and function of spinal locomotor circuitry.
Traditionally, motor neurons are thought to be solely the mediators of motor output from the spinal cord. However, as we have reported recently, stimulation of motor neuron axons in neonates can also trigger locomotor activity. This surprising and intriguing result suggests that motor neurons may play a more active role in the generation of locomotor activity than previously thought. Currently, we are aiming to explain how activation of motor neuron axons leads to this rhythmic activity. Unraveling the functional organization of spinal motor circuitry is critical both to our understanding of normal motor function, and perturbations of this system that occur in motor neuron diseases.
Dysfunction of motor circuits leads to severe deficits in neurodegenerative disease of Spinal Muscular Atrophy (SMA).
Spinal muscular atrophy is an inherited motor neuron disease caused by deficiency of SMN protein due to a mutation of the Survival Motor Neuron 1 (SMN1) gene. SMA affects newborn infants and is the most common inherited disorder lethal to infants and newborns. SMA is characterized by degeneration of motor neurons in the spinal cord and skeletal muscle atrophy. Life expectancy in the most severe cases is only 1 to 2 years. While much is known about the genetic causes of the disease, less information is available on the physiological alterations that explain the severity of motor symptoms displayed by affected individuals. The long-term objective of our research is to better understand early physiological changes in SMA in the hope that this will serve as a basis for uncovering causally related mechanisms which may be used as novel therapeutic approaches.
In neurodegenerative diseases, abnormalities of synaptic connectivity are thought to account for early clinical deficits. Dysfunction of specific, vulnerable neuronal populations may precipitate secondary changes in neural circuits that could exacerbate neuronal dysfunction. However, in many disease models, the primary targets and the precise sequence of functional and cellular changes that initiate the disease process remain unclear. Advances in our understanding of the genetic basis of heritable, motor neuron diseases such as SMA have also made it possible to model these disorders in mice.
We are currently concentrating our efforts on mouse models of SMA that closely mimic severe forms of the disease in infants. Mutant SMN-deficient mice exhibit severe motor abnormalities at birth and die within two weeks. To date, the majority of SMA studies have focused on molecular aspects of motor neuron degeneration and on changes at the neuromuscular junction. Little is known however, about the pathophysiology of the disease as it relates to spinal cord circuitry and motor neuron activity. Our studies have shown that there are significant defects in the sensory-motor circuitry. The reduced synaptic responses in spinal motor neurons raises the possibility that dysfunction of neuronal partners to motor neurons may contribute to the progression of SMA, and so provide a novel cellular target for therapeutic development. To address this, we are currently studying the effects of the SMN deficiency in specific neuronal populations.
Aleksandra Vukojicic, MSc
Postdoctoral Research Fellow/Scientist