Research Faculty

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Education and Training
1991 B.Sc.(Hons), Physiology, University College London (UCL), UK
1992 M.Sc. Neurological Science, University College London (UCL), UK
1997 Ph.D. Imperial College School of Medicine, UK

George Z. Mentis, Ph.D.
Assistant Professor of Pathology and Cell Biology
Research Summary

Developmental organization of motor neuronal circuitry

Spinal motor neurons serve as mediators of motor output from the spinal cord and their activity is modulated by a network of spinal neurons, known as the central pattern generator (CPG), which is responsible for the coordinated motor output that comprises locomotion.
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: (i) the spinal cord of young mice can survive for many hours under in vitro conditions, providing excellent access for pharmacological, electrophysiological and optical investigations; (ii) the isolated neonatal mouse spinal cord can generate locomotor-like activity in vitro, in response to stimulation of the brainstem, dorsal and ventral roots, as well as by application of pharmacological agents; and equally important, (iii) it is a genetically tractable system in which we have available molecular markers to identity and manipulate spinal neurons to study their role in the formation and function of spinal locomotor circuitry.
Traditionally, motor neurons are thought to be only 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 an active role in the generation of locomotor activity. To explain how motor neuron stimulation leads to this rhythmic activity, we must first understand the connections motor neurons make with each other and with spinal interneurons. Unraveling the functional organization of spinal motor circuitry is critical both to our understanding of normal motor function and the perturbation of this system that occurs in motor neuron disease.

Spinal Muscular Atrophy

To understand the role of spinal motor neurons in normal motor behavior, we must first describe the local circuitry in which they function. These same functional connections are undoubtedly perturbed in SMA, and must be understood in the context of disease models if function is to be protected or restored.
Advances in our understanding of the genetic basis of heritable, motor neuron diseases such as SMA and Amyotrophic Lateral Sclerosis (ALS) have also made it possible to model these disorders in mice. We are using these models to elucidate the cellular pathophysiology of motor neuron disorders using many of the same approaches we employ in the study of spinal motor development.
We are currently concentrating our efforts on a mouse model of SMA (SMN-Δ7) that closely mimics a severe form of the disease in infants. Mutant SMN-Δ7 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 about the pathophysiology of the disease as it relates to spinal cord circuitry and motor neuron activity. To address this, we are actively characterizing the effects of the SMN deficiency on the intrinsic properties and synaptic activation of SMN-Δ7 motor neurons. The experiments are performed using an intact spinal cord preparation in vitro that can be studied throughout the limited life span (2 postnatal weeks) of the SMN-Δ7 mutant animals.
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 degeneration of pre-motor neurons may contribute to the progression of SMA, and so provide a novel cellular target for therapeutic development.
Selected Publications

Lotti F., Imlach W.L., Saieva L., Beck E.S., Hao le T., Li D.K., Jiao W., Mentis G.Z., Beattie C.E., McCabe B.D., Pellizzoni L. (2012) An SMN-dependent U12 splicing event essential for motor circuit function. Cell. 151: 440-454.

Mentis G.Z., Blivis D., Liu W., Drobac E., Crowder M.E., Kong L., Alvarez F.J., Sumner C.J., O'Donovan M.J. (2011) Early functional impairment of sensory-motor connectivity in a mouse model of Spinal Muscular Atrophy. Neuron 69: 453-467.

Mentis G.Z., Alvarez F.J., Shneider N.A., Siembab V.C., O'Donovan M.J. (2010). Mechanisms regulating the specificity and strength of muscle afferent inputs in the spinal cord. Ann N Y Acad Sci. 1198: 220-30.

Shneider N.A.*, Mentis G.Z.*, Schustak J., O'Donovan M.J. (2009). Sensorimotor synapses form with normal specificity despite abnormal muscle spindle development in the mouse spinal cord. J. Neurosci. 29: 4719-35.
* equal contribution

Jean-Xavier C., Mentis G.Z., O'Donovan M.J., Cattaert D, Vinay L. (2007). The dual personality of GABA/glycine-mediated depolarizations in the immature spinal cord. Proc. Natl. Acad. Sci. U S A, 104: 11477-11482.

Personius K.E., Chang Q., Mentis G.Z., O'Donovan M.J., Balice-Gordon R.J. (2007). Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination. Proc. Natl. Acad. Sci. U S A, 104: 11808-11813.

Mentis G.Z., Siembab V.C., Zerda R., O'Donovan M.J., Alvarez F.J. (2006). Primary afferent synapses on developing and adult Renshaw cells. J. Neurosci. 26: 13297-13310.

Mentis G.Z., Alvarez F.J., Bonnot A, Richards D.S., Gonzalez-Forero D, Zerda R, O'Donovan M.J. (2005). Noncholinergic excitatory actions of motoneurons in the neonatal mammalian spinal cord. Proc. Natl. Acad. Sci. U S A, 102: 7344-7349.

Honors and Awards

2006 FARE Award (Fellows Award for Research Excellence) at NIH

2010 1st Audrey Lewis Young Investigator Award from FSMA (Families of SMA)
Committees , Council, and Professional Society Memberships

Society for Neuroscience (SfN)
Federation of European Neuroscience Societies (FENS)

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