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Deciphering the Locomotor Network: The Role of Spinal Cord Interneurons
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Developmental Genetics)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the spinal cord, an intricate neural network generates and coordinates the patterning of limb movements during locomotion. This network, known as the locomotor central pattern generator (CPG), comprises of various cell populations that together orchestrate the output of motor neurons. Identification of CPG neurons through their specific gene expression is a valuable tool that can provide considerable insight to the character, intrinsic properties and role of a population, which represents a step toward understanding locomotor circuit function and correlating neural activity to behaviour. We selectively targeted two inhibitory CPG populations to investigate their molecular characteristics, circuitry and functional role; Renshaw cells (RCs) marked by their specific expression of the cholinergic nicotinic receptor α2 (Chrna2) and a subset of the dI6 population derived by their selective expression of the Doublesex and mab-3 related transcription factor 3 (Dmrt3).

We found that RCs have hyperpolarisation-activated cation (Ih) and small calcium-activated potassium (ISK) modulatory currents that differentially regulate their excitation and firing properties, which influence the instantaneous feedback to motor neurons through the recurrent inhibition circuit. Due to previous difficulties isolating RCs from the surrounding locomotor circuits, their functional role remains poorly defined. For the first time, we selectively silenced RC inhibition and found that all aspects of motor behaviour, including coordination and gait were normal. The deletion of RC signalling instead altered the electrical and synaptic properties of the recurrent inhibitory circuit, suggesting that developmental plasticity compensates for the loss of RC inhibition.

We reveal Dmrt3 neurons comprise a population of glycinergic inhibitory, spike-frequency adapting commissural interneurons active during locomotion. Conditional silencing of the Dmrt3 population resulted in considerable gait abnormalities in the neonatal and adult mouse. This manifested as an uncoordinated CPG output in vitro, impaired limb coordination in pups and increased fore- and hindlimb synchrony in adults that was exacerbated at faster locomotor speeds. Dmrt3 mediated inhibition subsequently impacts locomotion and suggests the Dmrt3 population contribute to coordinating speed dependent left-right limb alternation. This thesis provides cellular, circuit and behavioural insights into the Renshaw cell and Dmrt3 populations and enhances our knowledge regarding their probable function within the locomotor CPG.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1272
Keyword [en]
Locomotion, central pattern generator, mouse, gait, recurrent inhibition, Renshaw cell, Dmrt3, Chrna2
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-305601ISBN: 978-91-554-9741-5OAI: oai:DiVA.org:uu-305601DiVA: diva2:1040162
Public defence
2016-12-16, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2016-11-25 Created: 2016-10-19 Last updated: 2016-11-28
List of papers
1. Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents I-h and I-SK
Open this publication in new window or tab >>Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents I-h and I-SK
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2015 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 41, no 7, 887-898 p.Article in journal (Refereed) Published
Abstract [en]

Renshaw 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 (RCs2) in the mouse spinal cord. Immunohistochemistry and electrophysiological characterization of passive and active RCs2 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 RCs2 constitute an electrophysiologically stereotyped population with a resting membrane potential of -50.5 +/- 0.4mV and an input resistance of 233.1 +/- 11M. We identified a ZD7288-sensitive hyperpolarization-activated cation current (I-h) in all RCs2, contributing to membrane repolarization but not to the resting membrane potential in neonatal mice. Additionally, we found RCs2 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 RCs2 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.

Keyword
interneurons, mouse, nicotinic acetylcholine receptor alpha2, recurrent inhibition, spinal cord
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-252184 (URN)10.1111/ejn.12852 (DOI)000352540800003 ()
Available from: 2015-05-06 Created: 2015-05-04 Last updated: 2016-10-26Bibliographically approved
2. Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell - motor neuron circuit
Open this publication in new window or tab >>Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell - motor neuron circuit
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(English)Article in journal (Refereed) Submitted
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-305237 (URN)
Available from: 2016-10-19 Created: 2016-10-13 Last updated: 2016-10-26
3. Dmrt3 derived spinal cord neurons regulate locomotor coordination across different speeds
Open this publication in new window or tab >>Dmrt3 derived spinal cord neurons regulate locomotor coordination across different speeds
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(English)Manuscript (preprint) (Other academic)
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-305239 (URN)
Available from: 2016-10-19 Created: 2016-10-13 Last updated: 2016-10-26

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