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Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Kullander)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Kullander)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Kullander)
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2006 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 47, 12294-12307 p.Article in journal (Refereed) Published
Abstract [en]

Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6-8, which function as vesicular glutamate transporters (VGLUTs). Here, we show that VGLUT2 (Slc17a6) is required for life ex utero. Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior. Investigations at embryonic stages revealed that neural circuits in the location of the pre-Botzinger (PBC) inspiratory rhythm generator failed to become active. However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved. Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells. The functional deficit results from an inability of PBC neurons to achieve synchronous activation. In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles. Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator.

Place, publisher, year, edition, pages
2006. Vol. 26, no 47, 12294-12307 p.
Keyword [en]
central pattern generator, rhythm, glutamate, respiration, network, physiology, development, transmitter
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-14473DOI: 10.1523/JNEUROSCI.3855-06.2006ISI: 000242387800023PubMedID: 17122055OAI: oai:DiVA.org:uu-14473DiVA: diva2:42243
Available from: 2008-01-30 Created: 2008-01-30 Last updated: 2016-05-11Bibliographically approved
In thesis
1. Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models
Open this publication in new window or tab >>Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spinal neurons are important in several aspects motor control. For example, the neurons essential for locomotor movements reside in the ventral spinal cord. In this thesis, different motor control functions are being related to neuronal populations defined by their common expression of a gene.

First, a targeted disruption of the gene for vesicular glutamate transporter 2 (Vglut2/ Slc17a6) is described. The mutant animals die at birth because of their inability to breathe. The neuronal network in the brainstem, responsible for inspiration, was shown to become non-functional by the targeted deletion of Vglut2. To our surprise, it was still possible to induce rhythmic activity with normal left/right alternation in spinal cords isolated from VGLUT2-null embryos. Inconsistent reports of Vglut1 expression in the spinal cord made us re-evaluate the Vglut1 and Vglut2 expressions. While Vglut2 expression was widespread in the spinal cord, Vglut1 expression was restricted to a few cells dorsal to the central canal.  Taken together, the data suggest that, glutamatergic signaling is mandatory to drive the bilateral breathing, but not needed for coordination of basal alternating spinal locomotor rhythm.

Next, a screen for genes with restricted ventral expression was made. Some of the genes found could be connected to the characteristics of specific neuronal cell populations. For example, fast motor neurons were shown to express the genes Calca and Chodl. Further, we found the Chrna2 expression selectively in putative Renshaw cells. It seems likely that the gene product, the alpha2 subunit of the nicotinergic receptor, could be linked to the unique connection of motor neurons to Renshaw cells. We used the Chrna2 promoter to drive expression of Cre recombinase in a transgenic mouse. The Cre activity was present in most neurons labeled with Renshaw cell markers, which should make it a useful tool for functional studies of this population. The studies presented here show how the genes expressed in subsets of neurons can be used to target populations of neurons for functional studies of neuronal systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 45 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 497
acetyl choline, central nervous system, central pattern generator, Cre recombinase, development, genetic screen, glutamate, interneuron, motor neuron, mouse, mouse genetics, movement, network, neuronal network, nicotinic receptors, physiology, Renshaw cell, rhythm, spinal cord, transmitter
National Category
Neurosciences Neurosciences Physiology Physiology Physiology
Research subject
Developmental Neurosciences
urn:nbn:se:uu:diva-109889 (URN)978-91-554-7654-0 (ISBN)
Public defence
2009-12-11, B22, BMC, Husarg 3, Uppsala, 09:00 (English)
Available from: 2009-11-20 Created: 2009-10-29 Last updated: 2009-11-20Bibliographically approved

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Wallén-Mackenzie, ÅsaGezelius, HenrikEnjin, AndersKullander, Klas
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