The development of movement depends on the maturation of the spinal cord motor circuits. Embryonic motor output is characterized first by spontaneous activity resulting in fetal jerk movements that later become more rhythmic and show limb alternations. In newborns motor development then undergoes a period of reflex and postural maturation leading into coordinated weigh-bearing locomotion. All these changes occur as a consequence of different maturation phases of the spinal synaptic networks and more specifically of local interneurons that ultimately control motor neuron firing patterns and motor output. Our long term objective is to understand the development of these local spinal circuits. Advances in this field were hampered in the past by the diversity and complexity of spinal interneurons. Fortunately, the recent development of mouse models expressing genetically-encoded reporters to identify interneuronal lineages now permits their study through development and allowed new understanding of the principles that govern spinal interneuron development. Our work has been focusing on one lineage of embryonic interneurons, named V1, that provide inhibitory control to ipsilateral motoneurons. Previously, we showed that this group diversifies into different types of adult interneurons, including Renshaw cells and Ia inhibitory interneurons (IaINs) that provide respectively recurrent inhibition to the same motoneurons and reciprocal inhibition between motoneurons with antagonistic actions around single joints. These two interneurons thus perform critical, but different roles in motor control. A basic question is then what mechanisms diversify single embryological groups of interneurons into distinct functional classes in adult. Previous analyses on Renshaw cells provided some important insights, including that this specification might occur early in embryological development and that individual cell types acquire different synaptology and functions through the different phases of spinal cord development. In this proposal we aim to investigate the development of the large group of V1 interneurons, including IaINs, that are interposed in proprioceptive reflexes. The underlying hypotheses are that IaINs are a group of V1-interneurons specified by their early birth (simultaneously with Renshaw cells) to acquire in the embryo transient motor axon inputs and functions that are quite distinct from those in adult. We also hypothesize that later they shed these embryonic inputs and develop connectivity that allows them to mediate reciprocal inhibition. Therefore we propose three aims to find out their birth dates (aim1), their major synaptic inputs and outputs in embryo (aim2) and the maturation of the reciprocal inhibitory circuit postnatally (aim 3). A corollary of this work is that congenital deficits that result in arrested spinal network development do not necessary imply a network with immature adult connectivity, but more likely networks of different connectivity appropriate to an earlier developmental point. Therefore it is important to understand the nature of this earlier connectivity to better appreciate the diversity of neurological motor deficits expressed in newborns. PUBLIC HEALTH RELEVENCE The work proposed will study spinal cord development focusing on the neuronal networks that mediate the maturation of coordinate movements and locomotion. The study will use powerful new mouse genetic methodologies to analyze the cellular elements that organize this network during development. The research is thus guided towards understanding normal and abnormal motor development in newborn and infants

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-IFCN-F (04))
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Riddle, Robert D
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Emory University
Schools of Medicine
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Bikoff, Jay B; Gabitto, Mariano I; Rivard, Andre F et al. (2016) Spinal Inhibitory Interneuron Diversity Delineates Variant Motor Microcircuits. Cell 165:207-219
Siembab, Valerie C; Gomez-Perez, Laura; Rotterman, Travis M et al. (2016) Role of primary afferents in the developmental regulation of motor axon synapse numbers on Renshaw cells. J Comp Neurol 524:1892-919
Zhang, Jingming; Lanuza, Guillermo M; Britz, Olivier et al. (2014) V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion. Neuron 82:138-50
Richards, Dannette S; Griffith, Ronald W; Romer, Shannon H et al. (2014) Motor axon synapses on renshaw cells contain higher levels of aspartate than glutamate. PLoS One 9:e97240
Wootz, Hanna; Fitzsimons-Kantamneni, Eileen; Larhammar, Martin et al. (2013) Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. J Comp Neurol 521:1449-69
Alvarez, Francisco J; Benito-Gonzalez, Ana; Siembab, Valerie C (2013) Principles of interneuron development learned from Renshaw cells and the motoneuron recurrent inhibitory circuit. Ann N Y Acad Sci 1279:22-31
Wootz, Hanna; Fitzsimons-Kantamneni, Eileen; Larhammar, Martin et al. (2013) Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. J Comp Neurol 521:1449-69
van Zundert, Brigitte; Izaurieta, Pamela; Fritz, Elsa et al. (2012) Early pathogenesis in the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Cell Biochem 113:3301-12
Benito-Gonzalez, Ana; Alvarez, Francisco J (2012) Renshaw cells and Ia inhibitory interneurons are generated at different times from p1 progenitors and differentiate shortly after exiting the cell cycle. J Neurosci 32:1156-70
Chen, Weisheng V; Alvarez, Francisco J; Lefebvre, Julie L et al. (2012) Functional significance of isoform diversification in the protocadherin gamma gene cluster. Neuron 75:402-9

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