Immunohistochemical localization of group I and II metabotropic glutamate receptors in control and amyotrophic lateral sclerosis human spinal cord: upregulation in reactive astrocytes
Section snippets
Subjects
The spinal cords of 25 patients (selected from the Netherlands ALS tissue bank) were studied. Tissue was obtained and used in a manner compliant with the Declaration of Helsinki. Informed consent was obtained for the use of brain tissue. The clinical (derived from patients’ medical records) and neuropathological features are summarized in Table 1. Seventeen patients had a clinical and post-mortem neuropathological diagnosis of ALS (12 sporadic, sALS, and five familial type of ALS, FALS). All
Case material
The clinical and neuropathological characteristics of the subjects used in this study are summarized in Table 1. There were no significant differences between the two groups (ALS and normal controls) with respect to the variables of age, sex, post-mortem interval or storage duration (Mann–Whitney two-tailed U-test). None of the control patients had confounding neurological or neuropathological abnormalities that would be expected to interfere with our analysis of the spinal cord.
mGluR expression in human spinal cord
The patterns of
Discussion
The present study describes the regional and cellular distribution of group I and group II mGluR subtypes in normal and ALS spinal cord. The following observations were made. (1) Immunocytochemical analysis demonstrated expression of mGluR1α, mGluR5 and mGluR2/3 throughout the human spinal cord. mGluR1α showed the highest relative level of expression in ventral horn neurons (laminae VIII and IX), whereas intense mGluR5 immunoreactivity was observed within the dorsal horn (superficial laminae I
Acknowledgements
This work was supported by Telethon Italy Grant 1244 (M.V.C.) and Teding van Berkhout Fellowship of De Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie (E.A.) and Netherlands ALS Research Foundation (D.T.). We thank W.P. Meun and R. Visser for expert photography.
References (70)
- et al.
Distribution and developmental changes in metabotropic glutamate receptor messenger RNA expression in the rat lumbar spinal cord
Brain Res. Dev.
(1999) - et al.
Differential expression of rat and human type I metabotropic glutamate receptor splice variant messenger RNAs
Neuroscience
(1998) - et al.
LY379268, a potent and selective Group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal, cerebral ischaemia
Neurosci. Lett.
(1999) - et al.
Metabotropic glutamate receptor activation contributes to nociceptive reflex activity in the rat spinal cord in vitro
Neuroscience
(1996) Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice
Cell
(1995)- et al.
Neuroprotective activity of the potent and selective mGlu1a metabotropic glutamate receptor antagonist, (+)-2-methyl-4 carboxyphenylglycine (LY367385): comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlu1a and mGlu5 receptors
Neuropharmacology
(1999) - et al.
The involvement of metabotropic glutamate receptors in sensory transmission in dorsal horn of the rat spinal cord
Neuroscience
(1998) - et al.
The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms
Neurochem. Int.
(2000) - et al.
Functional switch from facilitation to inhibition in the control of glutamate release by metabotropic glutamate receptors
J. Biol. Chem.
(1998) - et al.
Interactions between metabotropic and ionotropic glutamate receptor agonists in the rat spinal cord in vivo
Neuropharmacology
(1995)
Nitric oxide synthases: roles, tolls, and controls
Cell
Group-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection
Neuropharmacology
Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody
Neurosci. Res.
Motor neuron–astrocyte interactions and levels of Cu, Zn superoxide dismutase in sporadic amyotrophic lateral sclerosis
Exp. Neurol.
The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations
Neuroscience
The metabotropic glutamate receptors: structure and functions
Neuropharmacology
Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis
Neurol. Sci.
Pharmacological agents acting at subtypes of metabotropic glutamate receptors
Neuropharmacology
Group I and II metabotropic glutamate receptor expression in cultured rat spinal cord astrocytes
Neurosci. Lett.
Measurement of protein using bicinchoninic acid
Anal. Biochem.
Metabotropic glutamate receptor subtype-1 alpha (mGluR1 alpha) immunoreactivity in ependymal cells of the rat caudal medulla oblongata and spinal cord
Neurosci. Lett.
Pre- and/or post-synaptic localisation of metabotropic glutamate receptor 1alpha (mGluR1alpha) and 2/3 (mGluR2/3) in the rat spinal cord
Neurosci. Res.
Role of group I metabotropic glutamate receptors in traumatic spinal cord white matter injury
J. Neurotrauma
The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis
Ann. Neurol.
Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury
J. Pharmacol. Exp. Ther.
Differential distribution of metabotropic glutamate receptors 1a, 1b, and 5 in the rat spinal cord
J. Comp. Neurol.
Activation of metabotropic glutamate receptors delays apoptosis of chick embryonic motor neurons in vitro
NeuroReport
Calcium-binding proteins, parvalbumin- and calbindin-D 28k-immunoreactive neurons in the rat spinal cord and dorsal root ganglia: a light and electron microscopic study
J. Comp. Neurol.
Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy
Eur. J. Neurosci.
Expression and signaling of group I metabotrophic glutamate receptors in astrocytes and microglia
J. Neurochem.
Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation
Neuroscience
Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta
J. Neurosci.
Metabotropic glutamate receptors and neuronal degeneration in culture
Adv. Neurol.
Cited by (144)
Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases
2022, Pharmacology and TherapeuticsThe tripartite glutamatergic synapse
2021, NeuropharmacologyCitation Excerpt :Regarding glutamatergic signalling and excitotoxicity, changes in the expression of mGluRs and iGluRs appear to be a typical reaction of astrocytes to various insults of central nervous system (Table 2). An important component of homeostatic response of astroglia, reported both in the model animals and human patients, is an increase in the expression and activity of mGluRs (Aronica et al., 2001; Geurts et al., 2003; Martorana et al., 2012; Planas-Fontanez et al., 2020; Umpierre et al., 2019). The neuroprotective effects caused by the activation of Group I and II receptors in reactive astrocytes include the enhancement of glutamate uptake (Battaglia et al., 2015; Peterson and Binder, 2020; Planas-Fontanez et al., 2020; Verkhratsky and Parpura, 2016) and release of glial neurotrophic factors, such as BDNF (Durand et al., 2017), glial-derived neurotrophic factor (Battaglia et al., 2015), and TGF-β (Planas-Fontanez et al., 2020; Spampinato et al., 2014).
Metabotropic glutamate receptor involvement in the pathophysiology of amyotrophic lateral sclerosis: new potential drug targets for therapeutic applications
2018, Current Opinion in PharmacologyCitation Excerpt :mGlu2 and mGlu3 receptors are mainly expressed in neurons of the lamina II of the dorsal horn in spinal cord neurons of healthy humans and ALS cases [29]. Immunoreactivity for mGlu2/3 receptors was also found, although to a lesser extent, in lamina IX and Clarke's column and in glial cells in the white matter of the control human spinal cord [29] and mGlu3 mRNA is also expressed in human spinal cord neurons in glial cells of the white matter [28]. Thus, mGlu3 receptors may reduce excitatory synaptic transmission, and consequently excitotoxicity, by reducing presynaptic glutamate release, and by increasing glutamate clearance from the synapse through an up-regulation of glial glutamate transporters [36–38].
In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis
2017, NeuropharmacologyCitation Excerpt :Group I receptors, that includes mGluR1 and mGluR5, are excitatory and their activation produces inositol-1,4,5-trisphosphate and diacylglycerol, with ensuing mobilization of intracellular Ca2+ and activation of protein kinase C (Pin and Duvoisin, 1995; Nicoletti et al., 2011). Group I metabotropic Glu receptors are actively involved in the regulation of important cellular pathways and several reports described mGluR1 and mGluR5 over-expression in the spinal cord of ALS patients and SOD1G93A mice (Aronica et al., 2001; Valerio et al., 2002; Anneser et al., 2004a,b), where they are implicated as contributing to degeneration of glial and neuronal cells (Valerio et al., 2002; Rossi et al., 2008; D'Antoni et al., 2011; Martorana et al., 2012). We have recently reported that activation of presynaptic mGluR1 and mGluR5 autoreceptors by submicromolar concentrations of the mixed mGluR1/5 agonist (S)-3,5-Dihydroxyphenylglycine (3,5-DHPG) promoted excessive Glu release in the spinal cord of SOD1G93A mice (Giribaldi et al., 2013).
- 1
The first two authors contributed equally to the present work.