Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation.
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.
Wallén-Mackenzie
Asa
A
Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, 751 23 Uppsala, Sweden.
Gezelius
Henrik
H
Thoby-Brisson
Muriel
M
Nygård
Anna
A
Enjin
Anders
A
Fujiyama
Fumino
F
Fortin
Gilles
G
Kullander
Klas
K
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D019521:Body Patterning; D004622:Embryo, Mammalian; D018756:GABA Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018684:Glycine Agents / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000502:physiology*; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D010507:Periodicity; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012125:Respiratory Center / Q000166:cytology*; D015656:Respiratory Mechanics / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology; D013331:Strychnine / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000172:deficiency / Q000502:physiology*
D018756:GABA Antagonists; D018684:Glycine Agents; D018040:Receptors, Neurokinin-1; D050599:Vesicular Glutamate Transport Protein 2; D014446:Tyrosine 3-Monooxygenase; D013331:Strychnine; D001640:Bicuculline