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Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.ORCID iD: 0000-0001-7167-9434
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.ORCID iD: 0000-0001-7782-0830
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.ORCID iD: 0000-0001-9768-9462
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2017 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 23, 5634-5647 p.Article in journal (Refereed) Published
Abstract [en]

When 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 α2 (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 or 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.

Place, publisher, year, edition, pages
2017. Vol. 37, no 23, 5634-5647 p.
Keyword [en]
ChAT, Chrna2, mouse, spinal cord, VIAAT
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-305237DOI: 10.1523/JNEUROSCI.0949-16.2017ISI: 000402907200007PubMedID: 28483975OAI: oai:DiVA.org:uu-305237DiVA: diva2:1038683
Funder
The Swedish Brain FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2016-10-19 Created: 2016-10-13 Last updated: 2017-08-14Bibliographically approved
In thesis
1. Deciphering the Locomotor Network: The Role of Spinal Cord Interneurons
Open this publication in new window or tab >>Deciphering the Locomotor Network: The Role of Spinal Cord Interneurons
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
Locomotion, central pattern generator, mouse, gait, recurrent inhibition, Renshaw cell, Dmrt3, Chrna2
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-305601 (URN)978-91-554-9741-5 (ISBN)
Public defence
2016-12-16, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 10:15 (English)
Opponent
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Available from: 2016-11-25 Created: 2016-10-19 Last updated: 2016-11-28

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Enjin, AndersPerry, SharnHilscher, Markus M.Nagaraja, ChetanLarhammar, MartinGezelius, HenrikLeão, Katarina E.Kullander, Klas
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