Navegando por Autor "Perry, Sharn"
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Artigo Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell - motor neuron circuit(2017-05-08) Enjin, Anders; Perry, Sharn; Hilscher, Markus M; Nagaraja, Chetan; Larhammar, Martin; Gezelius, Henrik; Eriksson, Anders; Leão, Emelie Katarina Svahn; Kullander, KlasWhen activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor alpha 2 (Chrna2) in mice to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in Renshaw cells. Loss of VIAAT from Chrna2Cre expressing Renshaw cells did not impact any aspect of drug-induced fictive locomotion in the neonatal mouse, nor did it change gait, motor coordination or grip strength in adult mice of both sexes. However, motor neurons from neonatal mice lacking VIAAT in Renshaw cells received spontaneous inhibitory synaptic input with a reduced frequency, showed lower input resistance and had an increased number of proprioceptive glutamatergic and calbindin labeled putative Renshaw cell synapses on their soma and proximal dendrites. Concomitantly, Renshaw cells developed with increased excitability and a normal number of cholinergic motor neuron synapses indicating a compensatory mechanism within the recurrent inhibitory feedback circuit. Our data suggest an integral role for Renshaw cell signaling in shaping the excitability and synaptic input to motor neurons.Artigo Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents Ih and ISK(2015) Perry, Sharn; Gezelius, Henrik; Larhammar, Martin; Hilscher, Markus M.; Lamotte d’Incamps, Boris; Leão, Emelie Katarina Svahn; Kullander, KlasRenshaw cells in the spinal cord ventral horn regulate motoneuron output through recurrent inhibition. Renshaw cells can be identified in vitro using anatomical and cellular criteria; however, their functional role in locomotion remains poorly defined because of the difficulty of functionally isolating Renshaw cells from surrounding motor circuits. Here we aimed to investigate whether the cholinergic nicotinic receptor alpha2 (Chrna2) can be used to identify Renshaw cells (RCs(α2)) in the mouse spinal cord. Immunohistochemistry and electrophysiological characterization of passive and active RCs(α2) properties confirmed that neurons genetically marked by the Chrna2-Cre mouse line together with a fluorescent reporter mouse line are Renshaw cells. Whole-cell patch-clamp recordings revealed that RCs(α2) constitute an electrophysiologically stereotyped population with a resting membrane potential of -50.5 ± 0.4 mV and an input resistance of 233.1 ± 11 MΩ. We identified a ZD7288-sensitive hyperpolarization-activated cation current (Ih) in all RCs(α2), contributing to membrane repolarization but not to the resting membrane potential in neonatal mice. Additionally, we found RCs(α2) to express small calcium-activated potassium currents (I(SK)) that, when blocked by apamin, resulted in a complete attenuation of the afterhyperpolarisation potential, increasing cellular firing frequency. We conclude that RCs(α2) can be genetically targeted through their selective Chrna2 expression and that they display currents known to modulate rebound excitation and firing frequency. The genetic identification of Renshaw cells and their electrophysiological profile is required for genetic and pharmacological manipulation as well as computational simulations with the aim to understand their functional role.