Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism
Introduction
Human and animal studies suggest that compensatory mechanisms in the basal ganglia motor circuit occur in the presymptomatic stage of Parkinson's disease (PD), in which motor signs (i.e., bradykinesia, rigidity and resting tremor) are not yet manifest in spite of extensive degeneration of nigrostriatal dopaminergic neurons (reviewed by Bezard et al., 2003, Brotchie and Fitzer-Attas, 2009). Unraveling the molecular nature and temporal profile of these mechanisms may shed new light into the pathophysiology of parkinsonism, and lay the groundwork for new therapeutic interventions aimed at delaying the clinical onset of the disorder. Two different categories of compensatory mechanisms have been identified in early parkinsonism, i.e. those enhancing the activity of surviving dopaminergic neurons, and those restraining the activity of the indirect pathway of the basal ganglia motor circuit (reviewed by Brotchie and Fitzer-Attas, 2009). Examples of compensatory changes influencing the activity of dopaminergic neurons include enhanced levels of tyrosine hydroxylase and L-aromatic amino acid decarboxylase, and reduced levels of the high affinity dopamine transporter (Zigmond et al., 1984, Uhl et al., 1994, Lee et al., 2000, Sossi et al., 2007). Interventions aimed at amplifying these mechanisms may accelerate degeneration of dopaminergic fibers because of the production of reactive oxygen species from endogenous dopamine (see Brotchie and Fitzer-Attas, 2009). Changes occurring within the indirect pathway are more “safe” and perhaps occur earlier in the course of the disease. The indirect pathway connects the input station, i.e. the neostriatum, with the output stations of the basal ganglia motor circuit (the internal globus pallidus and the substantia nigra pars reticulata) via the external globus pallidus (GPext) and the subthalamic nucleus (STN). In the indirect pathway, striatal GABAergic projection neurons make synaptic contacts with GPext neurons, which, in turn, send GABAergic projections to the STN. STN neurons send excitatory axons to the output stations, thereby restraining the activity of ventral motor thalamic neurons projecting to the cerebral cortex (reviewed by Conn et al., 2005).
In the neostriatum, the activity of projection neurons of the indirect pathway is negatively modulated by D2 dopamine (DA) receptors and positively regulated by A2A adenosine receptors, NMDA receptors, and mGlu5 metabotropic glutamate receptors. GABA release at the synapses between striatal projection neurons and GPext neurons is negatively modulated by mGlu4 receptors, as well as by MOR opiate receptors activated by enkephalins that are released from the terminals of striatal projection neurons (reviewed by Conn et al., 2005). CB1 cannabinoid receptors are co-localized with D2 receptors in striatal projection neurons of the indirect pathway, and are also expressed on axon terminals in the GPext (Gerfen et al., 1990, Mailleux and Vanderhaeghen, 1992, Szabo et al., 1998, Hermann et al., 2002, Mátyás et al., 2006, Crespo et al., 2008, Martín et al., 2008, Van Waes et al., 2012). The overall function of CB1 receptors is to inhibit the indirect pathway (Blume et al., 2013).
The following changes have been described in early stages of experimental parkinsonism: (i) a reduced membrane availability of the GluN2B subunit of NMDA receptors expressed by striatal projection neurons (Hallett et al., 2005); (ii) a reduced catabolism of endocannabinoids leading to an increased activation of CB1 receptors (Kreitzer and Malenka, 2007); and (iii) an enhanced production of enkephalins in axon terminals of striatal neurons projecting to the GPext (Herrero et al., 1995, Asselin et al., 1994, Nisbet et al., 1995, Gudehithlu et al., 1991). No data are available on the expression of mGlu4, mGlu5, A2A and CB1 receptors, in spite of the importance of these receptors as drug targets in the treatment of parkinsonism (Jones et al., 2013, Gasparini et al., 2013, Amalric et al., 2013).
Here, we report that parkinsonism induced by acute injection of haloperidol or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice is associated with transient changes in the expression of genes encoding for mGlu4 receptors, mGlu5 receptors, A2A receptors, CB1 receptors, and pre-proenkephalin-A (the peptide precursor of enkephalins), in the striatum.
Section snippets
Animals
C57BL mice (22–24 g, body weight) were purchased from Charles River (Calco, Italy). Grm4+/−(B6.129-Grm4tm1Hpn/J) mice, on a C57/BL6 background, were purchased from The Jackson Laboratory (Bar Harbor, ME). The Grm4−/− offspring of heterozygotes were used to establish colonies of Grm4−/− mice (see Fallarino et al., 2010). Mice were kept under environmentally controlled conditions (ambient temperature, 22 °C; humidity, 40%) on a 12 h light/dark cycle with food and water ad libitum. All experiments
Time-dependent changes in the expression of genes encoding for preproenkaphalin-A and mGlu4, mGlu5, CB1, and A2A receptors in the striatum following acute haloperidol injection
Mice treated with saline or haloperidol (1 mg/kg, s.c.) were killed at different time points for measurements of the transcripts encoding for preproenkephalin-A, mGlu4 receptors, mGlu5 receptors, CB1 receptors, and A2A adenosine receptors in the striatum. There was no difference in any of the transcripts between values obtained at 1 and 3 d following a single injection of saline. Thus, the two sets of values obtained in mice treated with saline were pooled and used for controls. Treatment with
Discussion
The two models we have used, i.e. mice challenged with MPTP or with a single injection of haloperidol, are far from human pathology but are useful for an accurate time-dependent analysis of changes in the expression of striatal genes occurring at early times following nigro-striatal damage or DA receptor blockade. We have found that striatal genes encoding for therapeutic targets in PD, such as A2A, mGlu4, and mGlu5 receptors (Conn et al., 2005, Johnson et al., 2009, Nicoletti et al., 2011,
References (61)
- et al.
Group III and subtype 4 metabotropic glutamate receptor agonists: discovery and pathophysiological applications in Parkinson's disease
Neuropharmacology
(2013) - et al.
Presymptomatic compensation in Parkinson's disease is not dopamine-mediated
Trends Neurosci.
(2003) - et al.
Distribution and synaptic localisation of the metabotropic glutamate receptor 4(mGluR4) in the rodent CNS
Neuroscience
(2002) - et al.
Pretreatment with subeffective doses of Rimonabant attenuates orexigenic actions of orexin A-hypocretin 1
Neuropharmacology
(2008) - et al.
Spontaneous release of acetylcholine in striatum is preferentially regulated by inhibitory dopamine D2 receptors
Eur. J. Pharmacol.
(1996) - et al.
The use of c-fos as a metabolic marker in neuronal pathway tracing
J. Neurosci. Methods
(1989) - et al.
Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease
Neuropharmacology
(2005) - et al.
Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain
Neuroscience
(2002) - et al.
Effects of L-DOPA on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum
Neuroscience
(1995) - et al.
Changes in mGlu5 receptor expression in the basal ganglia of reserpinised rats
Eur. J. Pharmacol.
(2006)
A2A receptor antagonists do not induce dyskinesias in drug-naive or L-dopa sensitized rats
Brain Res. Bull.
Particle detection, number estimation, and feature measurement in gene transfer studies: optical fractionators stereology integrated with digital image processing and analysis
Methods
c-Fos as a transcription factor: a stressful (re)view from a functional map
Neurochem. Int.
Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat
Brain Res. Dev. Brain Res.
Age-related loss of cannabinoid receptor binding sites and mRNA in the rat striatum
Neurosci. Lett.
Dichotomous organization of the external globus pallidus
Neuron
Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia
Neuroscience
Changes in metabotropic glutamate receptor 1-8 gene expression in the rodent basal ganglia motor loop following lesion of the nigrostriatal tract
Neuropharmacology
Development of allosteric modulators of GPCRs for treatment of CNS disorders
Neurobiol. Dis.
Metabotropic glutamate receptors: from the workbench to the bedside
Neuropharmacology
Preproenkephalin and preprotachykinin messenger RNA expression in normal human basal ganglia and in Parkinson's disease
Neuroscience
Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia
Neurobiol. Dis.
Dopamine D1 receptor modulation of glutamate receptor messenger RNA levels in the neocortex and neostriatum of unilaterally 6-hydroxydopamine-lesioned rats
Neuroscience
Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates
Neuroimage
A GABA immunocytochemical study of rat motor thalamus: light and electron microscopic observations
Neuroscience
Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum
Neuroscience
Striatal changes in preproenkephalin mRNA levels in parkinsonian monkeys
Neuroreport
Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice
J. Neurosci.
Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
J. Neurosci.
Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders
J. Neurochem.
Cited by (6)
Cystic fibrosis transmembrane conductance regulator-associated ligand protects dopaminergic neurons by differentially regulating metabotropic glutamate receptor 5 in the progression of neurotoxin 6-hydroxydopamine-induced Parkinson's disease model
2021, NeuroToxicologyCitation Excerpt :The experimental data have, however, been in consistent and in some cases, contradictory. Whereas some studies reported that levels of mGlu5 were increased in the caudo-putamen, caudate and striatum (STR) (Cannella et al., 2015; Kang et al., 2019; Price et al., 2010), other studies reported the opposite, and found decreased levels in the STR, substantia nigra pars compacta (SNpc) and ventral tegmental area (Crabbe et al., 2018; Kuwajima et al., 2007; Yu et al., 2001). Activation of mGlu5 by the agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), or the positive allosteric modulator VU0360172, has been shown to be neuroprotective by inhibition of caspase-dependent apoptosis in cell experiments and to provide neuroprotection in many animal models of central nervous system (CNS) injury, including PD (Sengmany and Gregory, 2016; Zhang et al., 2015).
Endogenous Opiates and Behavior: 2015
2017, PeptidesCitation Excerpt :Highlights: Acute morphine treatment alleviated tremor in MPTP-treated monkeys [1451]. Penk gene expression increased in the indirect pathway in acute mouse models of drug-induced parkinsonism [183]. Dual KOR-agonist/MOR-antagonist modulation reduced levodopa-induced dsyskinesia and corrected dysregulated striatal changes in the nonhuman primate model of Parkinson’s disease [1074].
mGlu<inf>5</inf>-GABA<inf>B</inf> interplay in animal models of positive, negative and cognitive symptoms of schizophrenia
2015, Neurochemistry InternationalCitation Excerpt :Therefore, our study is the first to show anti-cataleptic activity of mGlu5 PAM in haloperidol-induced catalepsy test. It seems plausible that CDPPB activates direct pathway of the basal ganglia motor circuit, in contrast to mGlu5 NAMs, that inhibit the indirect pathways (Cannella et al., 2015). This problem is open for further investigations.
Haloperidol-induced catalepsy as an animal model for parkinsonism: A systematic review of experimental studies
2021, European Journal of NeuroscienceExpression of mGlu Receptor Genes in the Hippocampus After Intoxication with Trimethyltin
2019, Journal of Molecular NeuroscienceEarly-onset drug-induced parkinsonism after exposure to offenders implies nigrostriatal dopaminergic dysfunction
2018, Journal of Neurology, Neurosurgery and Psychiatry