Neuroscientist Dr. Brocard attempts to understand mechanisms by which spinal neural networks generate locomotor movements. His recent discoveries pave the way for a new concept in which autorhythmic pacemaker cells are critical in generating the locomotor rhythm. In addition to fundamental investigations, Frédéric Brocard also engages preclinical evaluation of new therapeutic strategies to reduce motor deficits.
Locomotor disorders profoundly impact quality of life of patients with spinal cord injury. Understanding the neuronal networks responsible for locomotion remains a major challenge for neuroscientists and a fundamental prerequisite to overcome motor deficits. Although we still have a limited insight into the way by which cellular and synaptic mechanisms cooperate to generate the locomotor rhythm, our recent investigations support the contribution of autorhythmic pacemaker cells in generating the locomotor rhythm. Our ongoing research address three specific aims.
Spasticity is one of the most common debilitating complications in patients with spinal cord injury (SCI) and is primarily attributed to excessive excitability of the spinal cord. Although the pathophysiological mechanisms are quite diverse, alterations in intrinsic motoneuron properties have been postulated to play a central role. In particular, the SCI predisposes motoneurons to express exuberant self-sustained plateau potentials, thereby contributing to uncontrollable muscle spasms. The persistent sodium current (INaP) is known to be one of the key conductances driving motoneuronal plateau potentials. In addition to being increased after SCI, the upregulation of INaP has been assumed to mediate abnormal slow tonic firing in motor units. Whether the INaP receives increased attention as a factor in spasticity, the molecular disturbances responsible for its dysfunction are fully unknown.
To tackle these issues, a multidisciplinary approach is used including genetic tools, electrophysiology (visual patch clamp, voltage sensitive dyes, EMG...), and immunohistochemistry (expression of Nav channels in the spinal cord).
1. BROCARD C, PLANTIER V, BOULENGUEZ P, LIABEUF S, BOUHADFANE M, VIALLAT-LIEUTAUD A, VINAY L, BROCARD F (2016). Calpain-mediated proteolytic cleavage of sodium channels after spinal cord injury increases the persistent sodium current and contributes to spasticity. Nat Medicine Apr;22(4):404-11.
2. CAZALS Y, BÉVENGUT M, ZANELLA S, BROCARD F, BARHANIN J, GESTREAU C (2015). KCNK5 channels in cochlear outer sulcus cells are indispensable for the maintenance of hearing. Nat Communications. Nov 9;6:8780.
3. BOUHADFANE M, KASZAS A, ROZSA B, HARRIS-WARRICK R, VINAY L, BROCARD F. (2015). Sensitization of lumbar motoneurons by the pain mediator bradykinin. Elife. 2015 Mar 17;4. doi: 10.7554/eLife.06195. [Epub ahead of print].
4. BOUHADFANE M, TAZERART S, MOQRICH A, VINAY L, BROCARD F, (2013).Sodium-mediated plateau potentials in lumbar motoneurons of neonatal rats. J Neurosci. 2013 Sep 25;33(39):15626-41.
5. BROCARD F, SHEVTSOVA. N, BOUHADFANE M, TAZERART S, HEINEMANN U, RYBAK I.A, VINAY L. (2013). Activity-dependent changes in extracellular Ca2+ and K+ reveal pacemakers in the spinal locomotor-related network. Neuron. 2013 Mar 20;77(6):1047-54.
6. BOS R, BROCARD F, VINAY L. (2011). Primary afferent terminals acting as excitatory interneurons contribute to spontaneous motor activities in the immature spinal cord. J Neurosci. Jul 13;31(28):10184-8.
7. BROCARD F, TAZERART S, VINAY L. (2010) Do pacemakers drive the central pattern generator for locomotion in mammals? Neuroscientist. 2010 Apr;16(2):139-55.
8. SADLAOUD K, TAZERART S, BROCARD C, JEAN-XAVIER C, PORTALIER P, BROCARD F, VINAY L, BRAS H. (2010) Differential maturational plasticity of the GABAergic and glycinergic synaptic transmission to rat lumbar motoneurons after spinal cord injury. J Neurosci. Mar 3;30(9):3358-69.
9. BROCARD F, RYCZKO D, FENELON K, HATEM R, GONZALES D, AUCLAIR F, DUBUC R. (2010) The transformation of a unilateral locomotor command into a symmetrical bilateral activation in the brainstem. J Neurosci. 2010 Jan 13;30(2):523-33.
10. TAZERART S, VINAY L, BROCARD F. (2008) The persistent sodium current generates pacemaker activities in the central pattern generator for locomotion and regulates the locomotor rhythm. J Neurosci. Aug 20;28(34):8577-89.
11. DUBUC R, BROCARD F, ANTRI M, FÉNELON K, GARIÉPY J.F, SMETANA R, MÉNARD A, LE RAY D, VIANA DI PRISCO G, PEARLSTEIN E, SIROTA M.G, DERJEAN D, ST-PIERRE M, ZIELINSKI B, AUCLAIR F, AND VEILLEUX D. (2008) Initiation of locomotion in lampreys. Brain Res Rev. Jan;57(1):172-82.
12. TAZERART S, VIEMARI JC, DARBON P, VINAY L, BROCARD F. (2007). Contribution of persistent sodium current to locomotor pattern generation in neonatal rats. J Neurophysiol. Aug;98(2):613-28. Article recommended as reading in Faculty of 1000. http://www.f1000biology.com/article....
13. BROCARD F, VERDIER D, ARSENAULT I, LUND J, KOLTA A. (2006). Emergence of intrinsic bursting in trigeminal sensory neurons parallels the acquisition of mastication in weanling rats. J. Neurophysiol, 96(5):2410-24.