Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury

doi:10.1016/j.neuroscience.2007.02.068

Neuroscience

Volume 147, Issue 2, 29 June 2007, Pages 469-490

https://doi.org/10.1016/j.neuroscience.2007.02.068 Get rights and content

Abstract

The expression of two vesicular glutamate transporters (VGLUTs), VGLUT₁ and VGLUT₂, was studied with immunohistochemistry in lumbar dorsal root ganglia (DRGs), the lumbar spinal cord and the skin of the adult mouse. About 12% and 65% of the total number of DRG neuron profiles (NPs) expressed VGLUT₁ and VGLUT₂, respectively. VGLUT₁-immunoreactive (IR) NPs were usually medium- to large-sized, in contrast to a majority of small- or medium-sized VGLUT₂-IR NPs. Most VGLUT₁-IR NPs did not coexpress calcitonin gene-related peptide (CGRP) or bound isolectin B4 (IB4). In contrast, ∼31% and ∼42% of the VGLUT₂-IR DRG NPs were also CGRP-IR or bound IB4, respectively. Conversely, virtually all CGRP-IR and IB4-binding NPs coexpressed VGLUT₂. Moderate colocalization between VGLUT₁ and VGLUT₂ was also observed. Sciatic nerve transection induced a decrease in the overall number of VGLUT₁- and VGLUT₂-IR NPs (both ipsi- and contralaterally) and, in addition, a parallel, unilateral increase of VGLUT₂-like immunoreactivity (LI) in a subpopulation of mostly small NPs. In the spinal cord, strong VGLUT₁-LI was detected, particularly in deep dorsal horn layers and in the ventral horns. VGLUT₂-LI was abundant throughout the gray spinal matter, ‘radiating’ into/from the white matter. A unilateral dorsal rhizotomy reduced VGLUT₁-LI, while apparently leaving unaffected the VGLUT₂-LI. Transport through axons for both VGLUTs was confirmed by their accumulation after compression of the sciatic nerve or dorsal roots. In the hind paw skin, abundant VGLUT₂-IR nerve fibers were observed, sometimes associated with Merkel cells. Lower numbers of VGLUT₁-IR fibers were also detected in the skin. Some VGLUT₁-IR and VGLUT₂-IR fibers were associated with hair follicles. Based on these data and those by Morris et al. [Morris JL, Konig P, Shimizu T, Jobling P, Gibbins IL (2005) Most peptide-containing sensory neurons lack proteins for exocytotic release and vesicular transport of glutamate. J Comp Neurol 483:1–16], we speculate that virtually all DRG neurons in adult mouse express VGLUTs and use glutamate as transmitter.

Section snippets

Animals

Male NMRI mice were used (body weight 25–30 g; n=19; B&K, Stockholm, Sweden). The animals were maintained under standard conditions on a 12-h light/dark cycle (light on, 7:00 a.m.), with water and food ad libitum.

The experiments were conducted in accordance with the Society for Neuroscience policy for the use of research animals, and were approved by the local ethical committee (Stockholms Norra Djurförsöksetiska Nämnd; #219/03, #385/04, #397/04). All experiments conformed to international

Dorsal root ganglia

In L4-5 DRGs of the naïve adult mouse around 11.9%±1% were VGLUT₁-IR (Fig. 1A, C;Table 1; control, n=4) and 65.4%±4.5% VGLUT₂-IR (Fig. 1B, D; Table 1; control, n=4). VGLUT₁-IR NPs of different sizes were observed, with areas ranging from 323 μm² to 2534 μm², and with a peak between 600 and 1400 μm², characteristic of medium- and large-sized DRG neurons (Figs. 1A, C; 2A). VGLUT₂ showed NP areas ranging from 83 μm² to 2169 μm², and a peak between 200 and 600 μm², thus favoring small- and

Discussion

In the present study we have analyzed the protein expression of two of the three known vesicular glutamate transporters in adult mouse DRGs and spinal cord. In DRGs, VGLUT₁ was present in some medium- to large-sized and VGLUT₂ in many small- to medium-sized neurons. Virtually all CGRP-IR and IB4-binding neurons were VGLUT₂-IR, supporting an important functional role of glutamate in sensory transmission, including nociception. The expression of the VGLUTs in DRGs was affected by peripheral nerve

Acknowledgments

The present study was supported by the Swedish Research Council (04X-2887), the Marianne and Marcus Wallenberg Foundation, the Knut and Alice Wallenberg Foundation. P.B. has been supported by Karolinska Institutet and the Austral University. We are grateful to Prof. Lars Terenius, Center for Molecular Medicine, Karolinska Institutet, Stockholm and to Professor Elvar Theodorsson, Department of Biomedicine and Surgery, Division of Clinical Chemistry, University Hospital, Linköping, Sweden, for

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Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury

Abstract

Section snippets

Animals

Dorsal root ganglia

Discussion

Acknowledgments

Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains

J Histochem Cytochem

The primary afferent depolarizing action of kainate in the rat

Br J Pharmacol

Molecular cloning of a novel brain-type Na(+)-dependent inorganic phosphate cotransporter

J Neurochem

Glutamate immunocytochemistry in the dorsal horn after injury or stimulation of the sciatic nerve of rats

Brain Res Bull

Vesicular glutamate transporters in the spinal cord, with special reference to sensory primary afferent synapses

J Comp Neurol

Functional cross-excitation between afferent A- and C-neurons in dorsal root ganglia

Neuroscience

Astrocytic exocytosis vesicles and glutamate: a high-resolution immunofluorescence study

Glia

Molecular and functional analysis of a novel neuronal vesicular glutamate transporter

J Biol Chem

Coexistence of glutamate and substance P in dorsal root ganglion neurons of the rat and monkey

J Comp Neurol

The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic transmission

J Neurosci

Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter

Science

Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model

Brain Res

Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin

J Comp Neurol

Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters

J Comp Neurol

Enrichment of glutamate-like immunoreactivity in primary afferent terminals throughout the spinal cord dorsal horn

Eur J Neurosci

Biochemistry and anatomy of transmitter glutamate

Vesicular glutamate transporter 2 is expressed in different nerve fibre populations that selectively contact pulmonary neuroepithelial bodies

Histochem Cell Biol

NPY Y1 receptors are present in axonal processes of DRG neurons

Exp Neurol

Phenotyping of sensory and sympathetic ganglion neurons of a galanin-overexpressing mouse-possible implications for pain processing

J Chem Neuroanat

Peripheral excitatory amino acids

Curr Opin Pharmacol

Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin

Neurosci Lett

Ultrastructural changes of the central scalloped (C1) primary afferent endings of synaptic glomeruli in the substantia gelatinosa Rolandi of the rat after peripheral neurotomy

J Neurocytol

Transient receptor potential ion channels as participants in thermosensation and thermoregulation

Am J Physiol Regul Integr Comp Physiol

Ultrastructural analysis of NMDA, AMPA, and kainate receptors on unmyelinated and myelinated axons in the periphery

J Comp Neurol

Fluorescent antibody methods

Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury

BMC Neurosci

Glutamate uptake

Prog Neurobiol

Properties and localization of glutamate transporters

Prog Brain Res

Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord

Proc Natl Acad Sci U S A

Peripheral glutamate release in the hindpaw following low and high intensity sciatic stimulation

Neuroreport

NMDA receptor antagonists: interactions with opioids

Acta Anaesthesiol Scand

Differential regulation of calcitonin gene-related peptide (CGRP) in regenerating rat facial nucleus and dorsal root ganglion

Eur J Neurosci

Modulation of the glutamatergic receptors (AMPA and NMDA) and of glutamate vesicular transporter 2 in the rat facial nucleus after axotomy

Neuroscience

A comparison of excitatory amino acid antagonists acting at primary afferent C fibres and motoneurones of the isolated spinal cord of the rat

Br J Pharmacol

Glutamate: a neurotransmitter in mammalian brain

J Neurochem

The expression of vesicular glutamate transporters defines two classes of excitatory synapse

Neuron

The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate

Proc Natl Acad Sci U S A

Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites

Differentiation-associated Na⁺-dependent inorganic phosphate cotransporter (DNPI) is a vesicular glutamate transporter in endocrine glutamatergic systems