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The Journal of Neuroscience, November 22, 2006, 26(47):12294-12307; doi:10.1523/JNEUROSCI.3855-06.2006

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Behavioral/Systems/Cognitive
Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Åsa Wallén-Mackenzie,¹ Henrik Gezelius,^1 * Muriel Thoby-Brisson,^2 * Anna Nygård,¹ Anders Enjin,¹ Fumino Fujiyama,³ Gilles Fortin,² and Klas Kullander¹

¹Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, 751 23 Uppsala, Sweden, ²Laboratoire de Neurobiologie Génétique et Intégrative, Institut Alfred Fessard, Centre National de la Recherche Scientifique, 91198 Gif sur Yvette, France, and ³Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

Correspondence should be addressed to either of the following: Klas Kullander, Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, P.O. Box 587, 751 23 Uppsala, Sweden, Email: klas.kullander{at}neuro.uu.se; or Gilles Fortin, Laboratoire de Neurobiologie Génétique et Intégrative, Institut Alfred Fessard, Centre National de la Recherche Scientifique, 91198 Gif sur Yvette, France, Email: gilles.fortin{at}iaf.cnrs-gif.fr

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-Bötzinger (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.

Key words: central pattern generator; rhythm; glutamate; respiration; network; physiology; development; transmitter

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Received Sept. 5, 2006; revised Oct. 10, 2006; accepted Oct. 11, 2006.

Correspondence should be addressed to either of the following: Klas Kullander, Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, P.O. Box 587, 751 23 Uppsala, Sweden, Email: klas.kullander{at}neuro.uu.se; or Gilles Fortin, Laboratoire de Neurobiologie Génétique et Intégrative, Institut Alfred Fessard, Centre National de la Recherche Scientifique, 91198 Gif sur Yvette, France, Email: gilles.fortin{at}iaf.cnrs-gif.fr

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