Several years ago, we made the observation that stimulation of the ventral roots can excite locomotor like activity and entrain disinhibited bursting in the neonatal mouse cord. This was surprising because no known circuitry existed to mediate these excitatory effects. We are currently using optogenetics to assess the role of motoneurons in locomotor rhythmogenesis and pattern formation. As part of this project, we will establish if stimulation of motor axons can activate glial cells within the motor nucleus and if such activation is involved in the excitation of spinal networks by ventral root stimulation. We are also using viruses to establish if motoneurons project to novel interneuronal targets that might mediate the activation of the CPG by motor axon stimulation. For this purpose we are using viruses to define the presynaptic inputs to hindlimb motoneurons using a modified rabies virus that passes from motoneurons to the cells immediately synapsing with motoneurons. We have also investigated the synaptic abnormalities in a mouse model of spinal muscular Atrophy (SMA). Previously we had shown that the number of terminals from muscle spindle afferents onto lumbosacral motoneurons was reduced in these animals. If this was due to abnormalities in the sensory afferents, then we would expect a similar loss of proprioceptive input to the other synaptic targets of muscle spindle afferents such as Renshaw interneurons. However, in contrast to the findings on motoneurons we found that afferent synapses were increased onto Renshaw cells inconsistent with the hypothesis of a generalized defect in sensory afferents in the SMA mouse. In a collaborative project with Huaibin Cai we examined synaptic function in a mouse model of amyotrophic lateral sclerosis in which a mutated vesicle-associated membrane protein-associated protein B (VAPB) accumulates on the postsynaptic membranes of C-terminals on spinal motoneurons. In these mice, spontaneous rhythmic discharges of motoneurons in the disinhibited cord were reduced and the response evoked in motoneurons by stimulation the interneurons giving rise to C-terminals was reduced in the mutant animals.

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Thirumalai, Vatsala; Behrend, Rachel M; Birineni, Swetha et al. (2013) Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy. J Neurophysiol 109:702-10
Aliaga, Leonardo; Lai, Chen; Yu, Jia et al. (2013) Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Hum Mol Genet 22:4293-305
Mentis, George Z; Alvarez, Francisco J; Shneider, Neil A et al. (2010) Mechanisms regulating the specificity and strength of muscle afferent inputs in the spinal cord. Ann N Y Acad Sci 1198:220-30
Bonnot, Agnes; Chub, Nikolai; Pujala, Avinash et al. (2009) Excitatory actions of ventral root stimulation during network activity generated by the disinhibited neonatal mouse spinal cord. J Neurophysiol 101:2995-3011
Shneider, Neil A; Mentis, George Z; Schustak, Joshua et al. (2009) Functionally reduced sensorimotor connections form with normal specificity despite abnormal muscle spindle development: the role of spindle-derived neurotrophin 3. J Neurosci 29:4719-35
O'Donovan, Michael J; Bonnot, Agnes; Mentis, George Z et al. (2008) Imaging the spatiotemporal organization of neural activity in the developing spinal cord. Dev Neurobiol 68:788-803