Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation

Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, 751 23 Uppsala, Sweden.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 12/2006; 26(47):12294-307. DOI: 10.1523/JNEUROSCI.3855-06.2006
Source: PubMed

ABSTRACT 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.


Available from: Klas Kullander, May 28, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains.
    Frontiers in Neuroanatomy 03/2015; 9:23. DOI:10.3389/fnana.2015.00023 · 4.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nerve injury induces a state of prolonged thermal and mechanical hypersensitivity in the innervated area, causing distress in affected individuals. Nerve injury-induced hypersensitivity is partially due to increased activity and thereby sustained release of neurotransmitters from the injured fibers. Glutamate, a prominent neurotransmitter in primary afferents, plays a major role in development of hypersensitivity. Glutamate is packed in vesicles by vesicular glutamate transporters (VGLUTs) to enable controlled release upon depolarization. While a role for peripheral VGLUTs in nerve injury-induced pain is established, their contribution in specific peripheral neuronal populations is unresolved. We investigated the role of VGLUT2, expressed by transient receptor potential vanilloid (TRPV1) fibers, in nerve injury-induced hypersensitivity. Our data shows that removal of Vglut2 from Trpv1-Cre neurons using transgenic mice abolished both heat and punctuate hyperalgesia associated with nerve injury. In contrast, the development of cold hypersensitivity after nerve injury was unaltered. Here, we show that, VGLUT2-mediated glutamatergic transmission from Trpv1-Cre neurons selectively mediates heat and mechanical hypersensitivity associated with nerve injury. Our data clarifies the role of the Trpv1-Cre population and the dependence of VGLUT2-mediated glutamatergic transmission in nerve injury-induced hyperalgesia.
    PLoS ONE 01/2015; 10(1):e0116568. DOI:10.1371/journal.pone.0116568 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Breathing in mammals is a seemingly straightforward behavior controlled by the brain. A brainstem nucleus called the preBötzinger Complex sits at the core of the neural circuit generating respiratory rhythm. Despite the discovery of this microcircuit almost 25 years ago, the mechanisms controlling breathing remain elusive. Given the apparent simplicity and well-defined nature of regulatory breathing behavior, the identification of much of the circuitry, and the ability to study breathing in vitro as well as in vivo, many neuroscientists and physiologists are surprised that respiratory rhythm generation is still not well-understood. Our view is that conventional rhythmogenic mechanisms involving pacemakers, inhibition, or bursting are problematic and that simplifying assumptions commonly made for many vertebrate neural circuits ignore consequential detail. We propose that novel emergent mechanisms govern generation of respiratory rhythm. That a mammalian function as basic as rhythm generation arises from complex and dynamic molecular, synaptic, and neuronal interactions within a diverse neural microcircuit highlights the challenges in understanding neural control of mammalian behaviors, many (considerably) more elaborate than breathing. We suggest that the neural circuit controlling breathing is inimitably tractable and may inspire general strategies for elucidating other neural microcircuits.This article is protected by copyright. All rights reserved
    The Journal of Physiology 11/2014; 593(1). DOI:10.1113/jphysiol.2014.277632 · 4.54 Impact Factor