1021018

review-article2021
NROXXX10.1177/10738584211021018The NeuroscientistSu et al.

Review
The Neuroscientist

Group 1 Metabotropic Glutamate

1­–16
© The Author(s) 2021

Receptors in Neurological and Psychiatric Article reuse guidelines:

Diseases: Mechanisms and Prospective

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DOI: 10.1177/10738584211021018
https://doi.org/10.1177/10738584211021018
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Li-Da Su1* , Na Wang2*, Junhai Han3, and Ying Shen4

Abstract
Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that are activated by glutamate in the
central nervous system (CNS). Basically, mGluRs contribute to fine-tuning of synaptic efficacy and control the accuracy
and sharpness of neurotransmission. Among eight subtypes, mGluR1 and mGluR5 belong to group 1 (Gp1) family,
and are implicated in multiple CNS disorders, such as Alzheimer’s disease, autism, Parkinson’s disease, and so on. In
the present review, we systematically discussed underlying mechanisms and prospective of Gp1 mGluRs in a group
of neurological and psychiatric diseases, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder,
epilepsy, Huntington’s disease, intellectual disability, Down’s syndrome, Rett syndrome, attention-deficit hyperactivity
disorder, addiction, anxiety, nociception, schizophrenia, and depression, in order to provide more insights into the
therapeutic potential of Gp1 mGluRs.

Keywords
metabotropic glutamate receptors, neurodegeneration disorder, psychiatric disorder, clinical trial, transgenic animal
model

Introduction channels (Kim and others 2003). Gp1 mGluRs are also
subject to allosteric binding of certain modulators, such
Metabotropic glutamate receptors (mGluRs) have an as positive allosteric modulators (PAMs) and negative
extracellular ligand-binding domain, a heptahelical mem- allosteric modulators (NAMs; Feng and others 2015),
brane structure, and a C-terminal tail. Different from which cause sensitization or desensitization of these
ionotropic glutamate receptors, mGluRs belong to receptors. PAMs and NAMs indirectly modulate gluta-
G-protein coupled receptors (GPCRs). Group 1 mGluRs mate transmission and are thereby used in clinical trials
(Gp1 mGluRs) consist of two members, mGluR1 and targeting related CNS disorders (Zoicas and Kornhuber
mGluR5. The locations of Gp1 mGluRs in the central 2019). Like other GPCRs, the activation of Gp1 mGluRs
nervous system (CNS) vary from isoform to isoform
(Alvarez and others 2000). mGluR1 is mainly expressed
in the hippocampus, cerebellum, and substantia nigra, 1
Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang
meanwhile mGluR5 is expressed in the hippocampus, University School of Medicine, Hangzhou, China
2
amygdala, olfactory bulb, striatum, nucleus accumbens, School of Medicine, Zhejiang University City College, Hangzhou,
septum, and dorsal horn (Abe and others 1992; Hubert China
3
School of Life Science and Technology, the Key Laboratory of
and others 2001; Jia and others 1999; Martin and other Developmental Genes and Human Disease, Southeast University,
1992; Romano and others 1995; Ryo and others 1993; Nanjing, China
Swanson and others 2005; Fig. 1). At synapses, mGluR1 4
Department of Physiology, Zhejiang University School of Medicine,
and mGluR5 are mainly located at postsynaptic terminals Hangzhou, China
(Fig. 2), although mGluR5 is also found at presynaptic *Li-Da Su and Na Wang have contributed equally to this work.
site and mediates the depletion of phosphatidylinositol-
Corresponding Authors:
4,5-bisphosphate (PIP2; He and others 2019). Ying Shen, Department of Physiology, Zhejiang University School of
The domain of Gp1 mGluRs bears orthosteric binding Medicine, 866 Yu Hang Tang Rd, Hangzhou 310058, China.
sites for endogenous glutamate (Koehl and others 2019). Email: yshen@zju.edu.cn
In Purkinje cells, glutamate binding of mGluR1 exerts Na Wang, School of Medicine, Zhejiang University City College,
slow currents (Zhou and others 2017), which are pro- Hangzhou 310015, China.
duced by coupled transient receptor potential C (TRPC) Email: wangna@zju.edu.cn
2 The Neuroscientist 00(0)

and the activation of protein kinase C (PKC; Maiese and

others 2008). Through these mechanisms, they induce
long-lasting changes of glutamatergic transmission,
including long-term depression (LTD) and long-term
potentiation (LTP), and neuronal excitability in cerebellar
Purkinje cells, the hippocampus, neocortex, dorsal and
ventral striatum, and spinal cord (Anwyl 1999; Ayala and
others 2008; Bellone and others 2008; Gladding and oth-
ers 2009; Jorntell and Hansel 2006; Kullmann and Lamsa
2008). Rich evidence demonstrates that Gp1 mGluRs
function in synaptogenesis, neuronal development, learn-
ing and memory, and neurodegeneration (Conn and Pin
Figure 1. The expression of Gp1 mGluRs in CNS. mGluR1 1997; Dale and others 2002; Nakanishi 1994; Pin and
expression is indicated by green shadow, and mGluR5 expression Duvoisin 1995; Pin and others 1994). The implications
pattern is indicated by blue shadow. This figure is modified from and mechanisms of mGluRs in several brain diseases
Lüscher and Huber (2010). SN = substantia nigra. have been reviewed within last decade (Amalric 2015;
Kumar and others 2015; Lüscher and Huber 2010;
Masilamoni and Smith 2018; Niswender and Conn 2010;
Ribeiro and others 2010a; Ribeiro and others 2017;
Srivastava and others 2020), focusing on individual dis-
eases (mainly Alzheimer’s disease and Parkinson’s dis-
ease). In the present review, we will combine previous
and more recent studies to discuss the underlying mecha-
nisms and prospective of Gp1 mGluRs in not only
Alzheimer’s disease and Parkinson’s disease but also
autism spectrum disorder, epilepsy, Huntington’s disease,
intellectual disability, Down’s syndrome, Rett syndrome,
attention-deficit hyperactivity disorder, addiction, anxi-
ety, nociception, schizophrenia, and depression.

Alzheimer’s Disease (AD)

Clinical studies reveal that levels of Gp1 mGluRs are
reduced in the hippocampus and the cortex in postmor-
tem brain of AD patients (Albasanz and others 2005),
although one study shows no difference between AD and
control groups at early stages (Ishibashi and others 2019).
To clarify the controversy, longitudinal observations are
required to determine the changes of Gp1 mGluRs asso-
Figure 2. The distribution of Gp1 mGluRs at glutamatergic ciated with AD progression. Indeed, the reduction of
synapse. Gp1 mGluRs are mostly localized postsynaptically and mGluR1 occurs in cases with the progression of AD
promote a calcium influx upon their activation and contribute (Albasanz and others 2005). Moreover, reduced mGluR5
to LTP/LTD induction. mGluR5 also modulates synaptic was found in 16-month-old Tg-ArcSwe mice, an AD
release probability by depleting PIP2. The astrocytes also mice model, when compared with control mice (Fang and
express mGluR5.
others 2017), and in the hippocampus of mild AD patients
when compared with age-matched controls (Mecca and
by glutamate or allosteric ligands causes conformational others 2020).
changes of extracellular domain and produces coupled The association of Gp1 mGluRs with AD progression
G-protein signaling, which relays to multiple downstream has been investigated to a good extent. In AD, amyloid
molecules (Jojart and others 2020; Niswender and Conn hypothesis holds amyloid-β (Aβ) peptide as the prime
2010). Upon the binding of glutamate or modulators, causative of AD pathology (Hardy and Selkoe 2002;
Gp1 mGluRs activate phospholipase C-γ (PLC-γ), gen- Tanzi and Bertram 2005), as shown by disruptive effects
erate inositol triphosphate (IP3) and diacylglycerol of Aβ40 and Aβ42 on synaptic transmission and brain
(DAG), and trigger a local rise of intracellular calcium connectome (Crews and Masliah 2010; Holtzman and
Su et al. 3

others 2012). Basically, it is speculated that Gp1 mGluRs LTD in cultured neurons (Hsieh and others 2006).
mainly influence Aβ and amyloid precursor protein Differently, Yang and others (2016) reported that mGluR-
(APP), which creep synapse loss, cognitive decline, and LTD is unaltered by Aβ application but blocked by APP/
silencing of brain circuits of AD (Overk and Masliah PS1 mutation. The experimental objects may explain the
2014; Palop and Mucke 2010). Still, the role of Gp1 controversy. It is possible that an unknown mechanism
mGluRs in AD is paradoxical: they may either prevent or compensates the short-term effect of Aβ on mGluR-LTD,
promote the progression of AD depending on distinct which is yet impaired by chronic accumulation of Aβ
conditions. The activation of Gp1 mGluRs accelerates with aging. In addition, a recent study provides evidence
non-amyloidogenic processing of APP and protects from showing the role of mGluR5 at the early stage of AD: the
Aβ-mediated neurotoxicity (Jolly-Tornetta and others release probability of hippocampal synapses is reduced
1998; Meziane and others 1998), suggesting that the acti- in APP/PS1 mice due to mGluR5-mediated depletion of
vation of Gp1 mGluRs may be a potential strategy for PIP2 (He and others 2019).
reversing pathological changes in AD patients. In con- Accordingly, Gp1 mGluRs participate in AD by regu-
trast to this finding, other studies demonstrated that Gp1 lating synaptic function through a series of downstream
mGluRs and their upstream or downstream proteins and upstream signaling pathways. Therefore, some antag-
together worsen AD progression. mGluR1 stimulation onists or modulators of Gp1 mGluRs have been taken in
can increase APP secretion and leads to accumulation of therapeutic treatment of AD. For example, 2-chloro-4-
Aβ (Nitsch and others 1997), which is mediated by the ((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imid-
release of arachidonic acid via intracellular Ca2+ mobili- azol-4-yl)ethynyl)pyridine (CTEP), a mGluR5-selective
zation and ultimately triggers the formation of neurofi- NAM (Lindemann and others 2011; Lindemann and oth-
brillary tangles, a pathological hallmark of AD (Tsai and ers 2015), is proved to be effective for the treatment of
others 2005). More studies revealed the interaction AD, at least in APPs/PS1 mouse model of AD (Hamilton
between Aβ and mGluR signaling on neuronal function and others 2016). Unfortunately, very few medicines
and structure. Soluble Aβ binds cellular prion protein have perfect effect for AD due to side effects or low effi-
(PrPC) during AD pathophysiology (Haas and others ciency, although more and more clinical candidates
2014), and Aβ-PrPC complex activates mGlu5 to disrupt related to Gp1 mGluRs are found. After all, Gp1 mGluRs
neuronal function (Um and others 2013). Thus, mGlu5 is are not the direct cause of AD while they play regulatory
a co-receptor for Aβ binding to PrPC to disrupt normal roles. This explains why Gp1 mGluRs-dependent medi-
neuronal signaling and function. This conclusion is con- cines cannot provide the radical cure for AD. In fact, the
firmed by the finding that mGluR5 deletion improves immunotherapy that uses antibody to bind parenchymal
AD pathogenesis and cognitive decline in APP/PS1 Aβ becomes popular for the treatment of AD (Sevigny
(Presenilin 1) mice (Hamilton and others 2014). and others 2016). Still, unraveling cellular mechanisms
It appears that the change of Gp1 mGluRs-dependent of Gp1 mGluRs in AD helps discover a new medicine to
synaptic plasticity is one culprit for cognitive impairment prevent AD progression. For example, we reported that
and dementia in AD patients. mGluR1-LTD is blocked in protein Numb and transferring receptor 1 (TFR1) are
APP/PS1 mice and suppressing pERK (phosphorylated able to modulate the trafficking and surface expression
extracellular regulated protein kinase) reverses mGluR1- of mGluR1 and mGluR5 (Wang and others 2019; Zhou
LTD failure (Yang and others 2016). mGluR1-LTD is and others 2015; Zhou and others 2017). Different from
facilitated by amyloid β (Aβ; Li and others 2009), which NAMs and PAMs, Numb and TFR1 do not interrupt
may explain the loss of structural and functional synapses Gp1 mGluRs in basal condition, instead they regulate
or spines (Kamikubo and others 2006; Nagerl and others the activity of mGluRs during neuronal plasticity.
2004; Shankar and others 2008) and the early learning Hence, these molecules may be potential therapeutic
and memory deficits in AD (Lüscher and Huber 2010). targets for AD.
Indeed, Aβ causes mushroom spine loss by overacting
mGluR5 in APP knock-in mouse model of AD (Zhang
and others 2015). Moreover, mGluR-LTD is associated
Parkinson’s Disease (PD)
with shrinkage or loss of dendritic spines (Zhou and oth- PD symptoms are characterized by motor rigidity, brady-
ers 2004). Consequently, mGluR dysfunction results in kinesia, tremor, and postural instability, which largely
compromised dendritic spines and synaptic memory (Ma arise through the progressive degeneration of dopamine
and Klann 2012; Oddo and others 2003), and blocking neurons in the substantia nigra. These dopamine neurons
this step may be a potential strategy for AD treatment. Yet are a key component of the basal ganglia, a highly orga-
the effect of Aβ on mGluR-dependent plasticity may be nized network of brain nuclei implicated in motor, limbic,
more complicated than expected. Exogenous Aβ leads to and cognitive functions. Gp1 mGluRs are expressed in
a removal of AMPARs that occludes mGluR-dependent basal ganglia nuclei, including dopaminergic neurons of
4 The Neuroscientist 00(0)

substantia nigra, striatal projection neurons and interneu- corroborated these results, showing that MPEP attenuates
rons, globus pallidus, and subthalamic nucleus (Conn parkinsonian motor deficits (Ambrosi and others 2010)
and others 2005). Due to their expressions, the associa- and decreases dyskinesias in several animal models of
tion between Gp1 mGluRs and PD was suggested two PD (Dekundy and others 2006; Johnston and others 2010;
decades ago. It is acknowledged that the expression of Mela and others 2007; Rylander and others 2010).
both mGluR5 and mGluR1 is altered in the striatum and Systemic administration of 3-[(2-methyl-1,3-thiazol-
in the substantia nigra of PD models of non-human pri- 4-yl)ethynyl] pyridine (MTEP), another NAM of
mate (Kaneda and others 2005; Morin and others 2013; mGluR5, is also highly protective against MPTP-induced
Ouattara and others 2010; Samadi and others 2008; neurodegeneration in non-human primates (Masilamoni
Sanchez-Pernaute and others 2008) and in parkinsonian and others 2011). It was further indicated that MTEP
patients with motor complications (Gregoire and others treatment protects noradrenergic and serotonergic neu-
2011). These findings were further strengthened by rons of locus coeruleus and dorsal raphe against MPTP
recent studies. Using positron emission tomography toxicity (Masilamoni and others 2011).
(PET), Kang and others (2019) showed that mGluR5 It appears that mGluR5 NAMs are more promising for
expression is increased in strategic dopaminergic brain the treatment of dyskinesia in PD patients compared to
regions of PD patients. PET imaging also shows that mGluR1. In support with this opinion, prevailing studies
pathological progressions are accompanied by dynamic showed that mGluR5 antagonists have significant anti-
changes of mGluR1 in A53T transgenic rat model of PD dyskinetic effects in rodent and non-human primate mod-
(Yamasaki and others 2016). Moreover, mGluR5 knock- els of PD (Dekundy and others 2006; Johnston and others
down was determined to decrease dyskinesia in an apha- 2010; Litim and others 2016) and some anti-parkinsonian
kia mouse model of PD (Garcia-Montes and others effects in 6-OHDA-treated rats (Breysse and others 2003).
2019). In addition, the binding potential of mGluR5 is More studies provide support toward the chronic use of
decreased in 6-OHDA rat model of PD (Crabbe and oth- mGluR5-related compounds as potential neuroprotective
ers 2018). drug in PD: (1) The combined treatment with MPEP and
Despite these findings, the precise roles of Gp1 L-DOPA significantly reduces dyskinesia intensity by
mGluRs in PD yet remain unclear. One possibility is that ~70% in de novo MPTP monkeys (Morin and others
Gp1 mGluRs influence basal ganglia synaptic transmis- 2013); (2) Fenobam, a mGluR5 NAM, reduces dyskine-
sion, as the activation of mGluR1/5 inhibits neuronal sias by ~50% in 6-OHDA rats and ~70% in MPTP mon-
activity in the striatum (Blaabjerg and others 2003) and keys (Ko and others 2014; Rylander and others 2010);
facilitates dopamine release from nigrostriatal terminals (3) Dipraglurant, a mGluR5 NAM, reduces the severity of
(Campusano and others 2002; Shimazoe and others dyskinesias in MPTP macaque model (Bezard and others
2002). Alternatively, Gp1 mGluRs cause Ca2+ oscillation 2014) and in PD patients (Tison and others 2016); (4)
and change the programming of transcriptional events mGluR5 antagonists (AFQ056-mavoglurant and ADX-
(Bradley and Challiss 2011), which further enhances the 48621-dipraglurant) show anti-dyskinetic functions and
activity of NR2B-containing NMDARs (Sarantis and are well tolerated in human trials (Stocchi and others
others 2015). Moreover, the absence of mGluR-LTD 2013). These preclinical studies provide evidence show-
results in a shift toward LTP within the striatum, and ing the effects of mGluR5 NAMs in PD therapy.
thereby leads to enhanced activity of indirect pathway
and excessive inhibition of movements in PD (Kreitzer
Autism Spectrum Disorder (ASD)
and Malenka 2007; Shen and others 2008). Thus, Gp1
mGluRs may participate in PD progression through ASD patients are characterized by the deficits in social
changing the excitatory drive of basal ganglia nuclei. communication and social interaction, repetitive behav-
Although the exact mechanism by which mGluR1/5 iors (American Psychiatric Association 2013), and motor
affect PD progression remains to be established, thera- behaviors (Gowen and Hamilton 2013). Although the
peutic implications of Gp1 mGluRs in PD have been pathogenic mechanism for ASD still remains elusive,
substantially studied (Nickols and Conn 2014). In a increasing evidence suggests that Gp1 mGluRs are impli-
6-OHDA-induced rodent model of PD, subchronic intra- cated in ASD according to the studies from ASD mouse
nigral administration of either LY367385, a mGluR1 models and patients (Auerbach and others 2011; Mercer
antagonist, or MPEP, a mGluR5 antagonist, significantly and others 2016; Seese and others 2014; Wang and others
slows down the degeneration of dopaminergic neurons, 2016; Wenger and others 2016). Seese and others (2014)
prevents 6-OHDA toxicity, and attenuates striatal dopa- found that the density of pERK1/2 is abnormally low in
mine depletion (Aguirre and others 2001; Battaglia and the hippocampus of BTBRT+ ltpr3tf/J mice with autistic
others 2002; Battaglia and others 2004; Vernon and oth- behaviors. Interestingly, MPEP can recover p-ERK1/2
ers 2005; Vernon and others 2007). Follow-up studies content and rescue long-term memory deficit (Huang and
Su et al. 5

others 2014), consistent with a previous study showing these antagonists to be ideal therapeutic drugs for ASD.
that mGluR5 increases neuronal ERK1/2 activity (Wang Importantly, ASD is caused by a combination of genetic
and others 2007). In Shank3 knockout mice, mGluR5- and environmental factors. Therefore, the treating with
Homer scaffolding is impaired which leads to abnormal antagonists of Gp1 mGluRs possibly breaks ASD into
cortico-striatal circuit, defective learning, and ASD-like individual symptom rather than as the whole. In this sce-
behaviors (Wang and others 2016). Deletion of 4E nario, a combination of multiple treatments is needed to
(eIF4E)-binding protein 2 (Eif4ebp2), which encodes efficiently alter the progression of ASD.
4E-BP2, leads to abnormal excitation-inhibition balance
and ASD-like behaviors. The antagonists of mGluR1
Epilepsy
(JNJ16259685) and mGluR5 (Fenobam) can recover
social interaction and repetitive behaviors of Eif4ebp2-/- It has been acknowledged that stimulation of Gp1
mice (Aguilar-Valles and others 2015). Gp1 mGluRs are mGluRs elicits ictal-like responses from normal hippo-
also involved in ASD patients (Wenger and others 2016). campus, which become persistent and show no fading
Copy number variants occur more frequently in mGluR even upon washout of the agonist (Zhao and others 2011;
network (over 270 genes) of ASD children than controls Zhao and others 2015). In fact, the long-lasting epilepti-
(Hadley and others 2014). It is noteworthy that mGluR form discharges induced by Gp1 mGluRs on hippo­
network genes are found in the 22q11.2 region and chro- campal network provides a model for the study of
mosome 21, which are involved in autistic behaviors in epileptogenesis. For example, increased expression of
Down’s syndrome. These data suggest that a second hit mGluR1/5 leads to epilepsy-associated focal cortical
derived from abnormal mGluR network may contribute dysplasias and human temporal lobe epilepsy (Aronica
to ASD phenotypes in patients with trisomy 21 or and others 2003) and chronic seizures display in trans-
22q11.2DS (Wenger and others 2016). Interestingly, the genic mice with the overexpression of mGluR1 (Pitsch
roles of Gp1 mGluRs in synaptic excitation may be sex and others 2007). It is noteworthy that the agonists of
dependent. Gabrb3 is one of the autism-linked genes mGluR1 and mGluR5 are uniformly convulsant and
expressed in the cerebellum (Hortnagl and others 2013). their antagonists are conversely anticonvulsant (Moldrich
Gabrb3 deletion exerts different results in male and and others 2003). The convulsant effects of Gp1 mGluRs
female mice: Neurons in mutant cerebellar nuclei of agonists may be produced by inhibiting cationic nonse-
males rather than females display enlarged mGluR1/5 lective channels or by potentiating NMDAR and/or
responses and accelerated spontaneous firing (Mercer AMPAR responses (Heidinger and others 2002). In addi-
and others 2016). tion, Gp1 mGluRs might be involved in epilepsy by
Some antagonists of Gp1 mGluRs are suggested to either impairing GABAergic potential (Marino and oth-
rescue ASD phenotypes in mouse models (Aguilar-Valles ers 2001) or enhancing presynaptic glutamate release
and others 2015; Belozertseva and others 2007; Molina- (Cartmell and Schoepp 2000). The anticonvulsant effects
Hernandez and others 2008; Thomas and others 2012). of mGluR1/5 antagonists are found in several seizure
JNJ16259685 restores impaired social behaviors only in rodent models. For example, mGluR1 antagonists,
Eif4ebp2 knock-out mice, but not in Shank2 knockout LY367385 and AIDA, robustly suppress generalized
rats (Modi and others 2018). The question remains motor seizures (Chapman and others 1999; Moldrich
whether agonists or PAMs of mGluR1 might be effica- and others 2003); potent antagonists of mGluR5, MPEP
cious in reversing social deficits in Shank2 knockout rats, and SIB-1893, suppress clonic seizures at low doses
given that Shank2 knockout mice show decreased (Chapman and others 2000). However, the effects of
NMDAR function. CFMTI, another selective mGluR1 MPEP are rather complicated, as it suppresses neuronal
antagonist, improves social interaction deficits induced firing triggered by DHPG at low doses (Gasparini and
by MK-801 in rats (Satow and others 2009), yet holding others 1999) but acts to modulate GABAergic transmis-
the potential of mGluR1 antagonists in reversing patho- sion and norepinephrine receptors at high doses
logical social interaction. There seem differential actions (Battaglia and others 2004; Mathiesen and others 2003).
of mGluR1 and mGluR5 on autistic behaviors. mGluR1 A group of phenylglycine-like mGluR1/5 antagonists
was characterized much less in the context of emotion have demonstrated potent anticonvulsant activity in
and behavior but more cognitive dysfunctions in mouse models of DHPG-induced limbic seizures. Intra-
models of ASD. In contrast, mGluR5 antagonists tend to cerebroventricular administration is required for these
act on cognitive deficits following high doses and their phenylglycine derivatives to demonstrate anticonvul-
effect are less severe than that of mGluR1 antagonists. sant activity. A series of aminopyridine derivatives have
Although pharmacological blockade of Gp1 mGluRs been used as potent noncompetitive antagonists with the
function emerges as potential therapeutic strategy for the high selectivity for mGluR1. LY456236 is one of such
treatment of ASD, overall there is still a huge gap for compound and is shown to be anticonvulsant against
6 The Neuroscientist 00(0)

sound-induced seizures, limbic seizures, focal seizure, of htt intranuclear inclusions (Ribeiro and others 2014);
and amygdala-kindled seizures (Shannon and others (3) decreased Ca2+ release and neuronal apoptosis are
2005). It is likely that there is no subtype difference in seen in cultured MSNs derived from HD mouse model
anticonvulsant actions, since the selective antagonists for when treated with MPEP (Tang and others 2003).
mGluR1 and mGluR5 are equally potent and non-sub- However, other studies suggest that the neuroprotective
type-selective antagonists appear to be the most potent effects of MPEP or MTEP are not mediated by mGluR5,
anticonvulsants (Merlin 2002; Stoop and others 2003). because these antagonists elicit same effects to mGluR5
Therefore, a synergic interaction between mGluR1 and knockout neuronal cultures (Lea and others 2005).
mGluR5 on neuronal bursts needs to be explored. Moreover, Gp1 mGluRs may have a dual function to
The underlying mechanisms for Gp1 mGluRs in epi- either promote neuro-protection or exacerbate neuronal
lepsy are still under investigation. PLC activation may be death, depending on neuronal type and drug incubation
a critical component of epileptogenic process. Inhibition paradigm (Bruno and others 2001). Overall, it is gener-
of PLC or PLCβ1 deletion prevents induction of ictal-like ally accepted that mGluR5 is important for HD-mediated
discharges (Chuang and others 2001). Furthermore, alterations in locomotor behavior. This conclusion was
agents that interfere with Ca2+ release from intracellular corroborated by more experiments using mGluR1/5-
stores prevent ictaform activity (McDonald and others related drugs. For example, CDPPB, one PAM of
1993) suggesting that mGluR-induced epileptogenesis mGluR5, is capable of delaying HD-related symptoms in
depends on intracellular Ca2+ mobilization. In addition, vitro and in vivo. Chronic treatment of CDPPB in
the inhibition of ERK1/2 phosphorylation prevents ictal- BACHD mice (another HD mouse model) significantly
like discharges, suggesting that mGluR-induced epilepto- activates cell signaling pathways important for neuronal
genesis also depends on ERK 1/2 response (Zhao and survival, prevents neuronal loss in the striatum, and
others 2004). decreases htt aggregation (Doria and others 2015). In
behaviors, CDPPB treatment is efficient to ameliorate
motor incoordination and to rescue memory deficits
Huntington’s Disease (HD) exhibited by BACHD mice (Doria and others 2015).
HD is an autosomal-dominant neurodegenerative disor- Importantly, no toxic effects or stereotypical behavior are
der caused by a poly-glutamine expansion in huntingtin observed upon CDPPB treatment (Doria and others
(htt) protein. Primary symptoms of HD include chorea, 2015). These data indicate that CDPPB is a promising
loss of cognition, psychiatric disturbance, and death. drug to treat HD.
Mutated htt is proposed to cause the progressive loss of It has been shown that several intracellular signaling
neurons in the caudate-putamen and neocortex of HD molecules are involved in the action of mGluR1/5 in
patient’s brain. Ample evidence indicates that mGluR1/5 HD. First, the attenuation of mGluR1/5 signaling
play essential roles in HD through interacting with htt observed in HdhQ111/Q111 mice is PKC dependent and
protein or cooperating with NMDAR. On one hand, only present in young asymptomatic mice (Ribeiro and
mGluR5 directly interacts with mutant htt protein others 2010b). It is possible that PKC-mediated
(Anborgh and others 2005), which functions in a knockin mGluR1/5 desensitization is protective, avoiding fur-
mouse model of HD (Ribeiro and others 2010b). On the ther increases in Ca2+ release that may result in increased
other hand, the activation of Gp1 mGluRs enhances cell death. Second, mGluR1/5 activates cell signaling
NMDAR-induced membrane depolarization and intracel- pathways, including ERK1/2, PI3K/Akt, and mamma-
lular Ca2+ accumulation in medium spiny neurons lian target of rapamycin (mTOR), which contribute to
(MSNs; Calabresi and others 1999). Consequently, the neuroprotection. Indeed, mGluR5 activation leads to
stimulation of mGluR1/5 facilitates the sensitization of higher levels of ERK and Akt phosphorylation in cul-
IP3 receptor and enhances Ca2+ release from intracellular tured HdhQ111/Q111 striatal neurons (Ribeiro and oth-
stores in HD mouse models (Ribeiro and others 2010b; ers 2010b). The phosphorylation of Akt may function to
Tang and others 2003). reduce htt aggregate formation and neuronal cell death
Likewise, the antagonists of Gp1 mGluRs, such as (Warby and others 2009). Third, CDPPB increases
MPEP, have been used to treat HD mouse models. mRNA level of BDNF in the cortex while it decreases
Basically, MPEP works well against HD: (1) MPEP neuronal loss and htt aggregation (Doria and others
increases survival time and improves rotarod perfor- 2015). Increasing BDNF level is probably an important
mance of HD mice, though it does not decrease htt aggre- neuroprotective mechanism activated by CDPPB, as
gate formation (Schiefer and others 2004); (2) the deletion BDNF promotes differentiation, plasticity, and survival
of mGluR5 in a mouse model of HD (HdhQ111/Q111) of neurons in the cortex and striatum (Poo 2001). Indeed,
improves rotarod performance and decreases the number behavioral performance is improved and disease
Su et al. 7

progression slows down when BDNF is over-expressed 2021), suggesting that they may coordinately control Arc/
in transgenic HD mice (Xie and others 2010). Arg3.1-depenent mGluR-LTD and the progress of ID.
There are few studies on the role of mGluRs in DS. It
is shown that mGluR5 expression is increased in the cere-
Other Disorders
bral cortex of DS patients (Oka and Takashima 1999).
Gp1 mGlus are also involved in other disorders, includ- Specifically, the expression of mGluR5 in hippocampal
ing intellectual disability (ID), Down’s syndrome (DS), astrocytes increased at the middle phase of gestation and
Rett syndrome (RTT), attention-deficit hyperactivity dis- it maintained postnatally (Iyer and others 2014). However,
order (ADHD), addiction, anxiety, nociception, schizo- there appears no correlation between mGluR5 increase
phrenia, and Renpenning syndrome. and the number of astrocytes in DS patients: a study using
Fragile X syndrome (FXS) is one of ID most studied same cohort of patients failed to detect difference in the
and is caused by the expansion of CGG repeats in Fmr1 expression of GFAP (Kanaumi and others 2013).
gene. Synaptic plasticity in the hippocampus has been The investigation on the involvement of mGluRs in
mostly studied in Fmr1 knockout mice, and the results RTT is also few. Mecp2 knockout mice display an altera-
showed that NMDAR-dependent LTP and LTD, the tion in protein synthesis after the induction of mGluR5-
prominent forms of plasticity, are unaltered in Fmr1 LTD (Tao and others 2016). Further analysis on the
knockout mice (Huber and others 2002). Hence, research genome-wide profile of ribosome-bound mRNAs dem-
attention was moved to mGluRs-dependent synaptic onstrates different expression in Mecp2 knockout mice:
plasticity and a definition of “mGluR theory” was derived the majority of mRNAs are upregulated in knockout
from compelling in vitro and in vivo evidence in FXS mice, suggesting that MECP2 acts as a repressor of gene
(Bear and others 2004). mGluR5-dependent plasticity is expression. Most affected genes upon Mecp2 loss are
exaggerated in Fmr1 knockout mice compared to wild involved in cytoskeleton organization and cell morpho-
type mice (Huber and others 2002), consistent with a fact genesis, which play key roles in the transport of synaptic
that both Fmr1 deletion and mGluR5 stimulation result in vesicles, spine morphology, and dynamics (Tao and oth-
increased protein synthesis. This finding led to a hypoth- ers 2016). NAMS for mGluR5 were used to chronically
esis that regulating mGluR5 activity may be beneficial treat Mecp2 knockout mice and this treatment signifi-
for the impairment caused by Fmr1 deletion. In fact, cantly reduced upregulated ribosome-associated mRNAs
crossing of Fmr1 knockout mice with mice heterozygous and improved phenotypes of Mecp2 knockout mouse
for mGluR5 induces the recovery of protein synthesis and (Tao and others 2016).
is able to rescue aberrant dendritic spines (Dolen and oth- The role of mGluRs in ADHD is even just at the
ers 2007). Therefore, many clinical trials have been beginning. A whole-genome analysis demonstrated
aimed at the efficacy of mGluR5 antagonists or NAMs in mutations in genes encoding for mGluRs: Grm5, Grm7,
FXS patients since then. Unexpectedly, most of trials and Grm8 deletions and Grm1 duplication were found
failed to discover any benefit in the defective behaviors in several patients (Elia and others 2011), suggesting
of subjects (Berry-Kravis and others 2018). Nevertheless, that up to 10% of ADHD cases may present variances in
other efforts are still continued to verify whether these mGluR network.
treatments could provide better results in individuals of mGluR1 and mGluR5 appear to be implicated in
different ages or within the duration of treatments. addiction via synaptic plasticity. mGlu-LTD may reverse
Besides FXS, Renpenning syndrome is a type of X-linked synaptic potentiation of cocaine in ventral tegmental
ID that shows microcephaly, short stature, small testes, area (VTA), which is required for subsequent synaptic
and specific facial dysmorphism (Kalscheuer and others adaptations in the nucleus accumbens (NAc; Bellone and
2003; Rejeb and others 2011). The mutations of polyglu- Lüscher 2006; Mameli and others 2009). mGluR1 needs
tamine-binding protein 1 (PQBP1) gene in human are to bind to Homer isoforms to induce LTD in the VTA.
demonstrated to be associated with Renpenning syn- When mGluR1-Homer interaction is disrupted, the plas-
drome (Ito and others 2009). A recent study demonstrated ticity in response to single injection of cocaine becomes
that the deletion of Pqbp1 interrupts eEF2K/eEF2 path- persistent and drives synaptic adaptations in the NAc
way and impairs mGluR-LTD and related behaviors (Mameli and others 2009).
(Shen and others 2021). This work not only reveals the mGluR5-knockout animals exhibited reduced level of
underlying mechanism of Renpenning syndrome but also anxiety (Brodkin and others 2002), and stress-induced
identifies PQBP1 as a new player in mGluR signaling and hyperthermia was attenuated by MTEP in wild-type mice
synaptic plasticity. Interestingly, both PQBP1 and FMRP but not in mGluR5 knockout animals, highlighting the
regulate the activity of eEF2 and subsequent de novo Arc/ involvement of mGluR5 in anxiety (Brodkin and others
Arg3.1 translation (Park and others 2008; Shen and other, 2002). In addition, mGluR5 expression was increased in
8 The Neuroscientist 00(0)

CA1 but decreased in CA3 region of the hippocampus in ketamine. Instead, the antidepressant actions of mGluR5
depression, indicating that mGluR5 is possibly engaged NAMs were blocked by depletion of 5-HT (Fukumoto
in the mechanism of depression (Wieronska and others and Chaki 2015; Palucha-Poniewiera and others 2014a).
2001). Thus, serotonergic transmission may be involved in the
mGluR5 may be involved in nociception following actions of mGluR5 NAMs.
tissue injury (Walker and others 2001) and in brain isch-
emia (Bao and others 2001). In the middle cerebral artery
Conclusions
occlusion (MCAO) experiment, both mGluR5 agonist
(CHPG) and antagonist (MPEP) have neuroprotective In this review, we discussed the roles of Gp1 mGluRs in
effects with different mechanisms: CHPG may limit the major neurodevelopmental, neurodegeneration, and
neuronal apoptosis after ischemia, while MPEP reduces psychiatric disorders. Some mechanisms are shared
neuronal damage and improves neurological recovery among different pathologies. However, determining
induced by ischemia. whether the defects are similar direction among different
Gp1 mGluRs are also implicated in schizophrenia. In disorders is more complicated due to the complexity of
the perinatal phencyclidine (PCP) model of schizophre- pathologies and animal models studied. Still, the devel-
nia, mGluR5 level is significantly increased in the pre- opment of specific pharmacological tools and transgenic
frontal cortex and the hippocampus, whereas hippocampal animals has greatly advanced our understanding to the
mGluR1α is reduced (Lum and others 2016). Hence, functions of Gp1 mGluRs in CNS disorders. Accordingly,
the disrupted expression of mGluR1 and mGluR5 may the antagonists or NAMs of Gp1 mGluRs, such as MPEP
underlie neurodevelopmental alterations after PCP treat- or CTEP, have been suggested as treatments for different
ment. In addition, the reduction of dysbindin-1, which pathologies with promising effects. For convenience, we
occurs in the brains of schizophrenia patients, leads to here listed kinds of agonists, antagonists, PAMs, and
impaired expression of Gp1 mGluRs, and the phosphory- NAMs of Gp1 mGluRs that have been used in animal
lation of ERK1/2 is also strikingly reduced during these models and patients in Table 1. However, clinical trials
processes (Bhardwaj and others 2015). Thus, dysbindin-1 still have controversial results, which may be biased by
may be another modulator of Gp1 mGluRs and the poten- small number of patients. In addition, prevailing drugs
tial target for the treatment of schizophrenia. mainly aim at the direct inhibition or activation of
Finally, recent work reveals the role of mGluR5 in mGluRs, which may bring about many side effects. For
depression, another psychiatric disease of great concern. example, Berry-Kravis and others (2018) summarized
First, PET scan indicated the decreased level of mGluR5 that PAMs and NAMs of mGluRs have been tested in
in several brain regions of patients with MDD comprehensive drug development programs undertaken
(Deschwanden and others 2011). Second, antidepressant for a wide range of neurodevelopmental disorder.
effects MPEP, MTEP, GRN-529, basimglurant, and DSR- However, none of the trials are able to unambiguously
98776 were demonstrated in animal models of depression demonstrate efficacy in the drug development for FXS
(Chaki and Fukumoto 2018). Full NAMs of mGluR5, and other neurodevelopmental disorders (Berry-Kravis
such as MTEP or MTEP, potentiated PCP-induced hyper- and others 2018). Still, we have very few knowledge to
locomotion in rodents (Gould and others 2016), presum- the role of Gp1 mGluRs on some diseases, such as RTT,
ably due to the inhibition of NMDAR. Interestingly, ADHD, anxiety, schizophrenia, and motor incoordina-
partial NAMs of mGluR5 also exerted antidepressant tion. Further efforts are needed to better understand how
effect without affecting PCP-induced hyperlocomotion the modulation of Gp1 mGluRs can be used in patients to
(Gould and others 2016). Thus, partial NAMs may be the ameliorate their symptoms, and more clinical trials on
better clinical target for safe. Although no statistical these diseases may bring us new hope.
effect was observed in the efficacy of basimglurant exam- Greater efforts have been made to achieve a general
ined in patients with MDD, a trend toward a beneficial view on mGluR network, mainly cooperative proteins
effect was found (Quiroz and others 2016). Therefore, and receptors (Fig. 3). These identified signaling mole-
further clinical studies are needed to evaluate mGluR5 cules provide new insights on the prospective of mGluRs
NAMs as antidepressant drugs. The antidepressant effects in neurological disorders, although their implications in
of mGluR5 NAMs were not antagonized by TrkB inhibi- the pathologies are not sufficient enough, mainly due to
tor (Iijima and others 2012) or mTOR inhibitor (Iijima technical and methodological limitations. Indeed, auxil-
and others 2012; Palucha-Poniewiera and others 2014b), iary proteins that modulate mGluRs activity in certain
and mGluR5 NAM did not affect mTOR cascade or syn- cellular processes may be better targets for related dis-
aptic protein (Palucha-Poniewiera and others 2014b). eases. For example, transmembrane AMPA receptor
Therefore, the neural mechanism for the antidepressant regulatory protein (TARP), which regulates the traffick-
effect of mGluR5 NAMs is distinct from that for ing of AMPARs, was considered to be a potential target in
 Table 1. Summary of Drugs Targeting Gp1 mGluR-Related Diseases.
Disease Drugs Selectivity Effect Model Reference

AD CTEP mGluR5 NAM Prevents cognitive impairment APP/PS1 mouse Lindemann and others 2011; Lindemann and others
2015
ASD JNJ16259685 mGlu1 antagonist Recue social interaction and repetitive Eif4ebp2 knockout mouse Aguilar-Valles and others 2015; Modi and others 2018
Fenobam mGlu5 antagonist behaviors
ASD CFMTI mGluR1 antagonist Improves social interaction MK-801 rat Satow and others 2009
Epilepsy LY367385 mGluR1 antagonists Suppress motor seizures DBA/2 mouse Chapman and others 1999
AIDA Lethargic mouse
Genetically epilepsy-prone rat
Epilepsy MPEP mGluR5 antagonists Suppress clonic seizures DBA/2 mouse Chapman and others 2000
SIB-1893 Lethargic mouse
Epilepsy LY456236 mGluR5 antagonist Inhibits clonic-tonic seizures DBA/2 mouse Shannon and others 2005
Inhibits limbic seizures SD rat
Decreases behavioral and electrographic
seizures
Decrease generalized seizures
PD LY367385 mGluR1 antagonist Slow degeneration of dopaminergic neurons 6-OHDA rodent Aguirre and others 2001; Ambrosi and others 2010;
MPEP mGluR5 antagonist Prevent striatal dopamine depletion MPTP monkey Breysse and others 2003; Dekundy and others 2006;
Attenuate parkinsonian motor deficits Parkinsonian rat and monkey Johnston and others 2010; Mela and others 2007;
Decrease dyskinesia Rylander and others 2010; Vernon and others 2007
PD MTEP mGluR5 NAM Reduces neurodegeneration MPTP non-human primate Masilamoni and others 2011
PD Fenobam mGluR5 NAM Reduces dyskinesia 6-OHDA rat Ko and others 2014; Rylander and others 2010
MPTP monkey
PD Dipraglurant mGluR5 NAM Reduces severity of dyskinesia MPTP macaque Bezard and others 2014; Tison and others 2016
PD patient
PD AFQ056-mavoglurant mGluR5 antagonists Reduce dyskinesia PD patient Stocchi and others 2013
ADX-48621-dipraglurant
HD MPEP mGluR5 antagonist Increases survival time R6/2 mouse Schiefer and others 2004
Improves rotarod performance
HD CDPPB mGlu5 PAM Prevents neuronal loss BACHD mouse Doria and others 2015
Decreases htt aggregation
Ameliorates motor incoordination
Rescues memory deficit
HD MTEP mGlu5 NAM Increases locomotor activity HdhQ111/Q111 HD mouse Ribeiro and others 2014
ID CTEP mGlu5 NAM Prolongs lifespan Fmr1 KO mouse Tao and others 2016
Reduces long breath-holding
Ameliorates inhibitory avoidance deficit
RTT CTEP mGlu5 NAM Improves lifespan Mecp2 KO mice Tao and others 2016
Ischemia MPEP mGluR5 antagonist Reduce infarct volume MCAO rat Bao and others 2001
CHPG mGluR5 agonist
Depression MPEP mGlu5 NAM Antidepressant action MDD rat Chaki and Fukumoto 2018
MTEP MDD patient
GRN-529
Basimglurant
DSR-98776

9
10 The Neuroscientist 00(0)

Figure 3. The upstream and downstream proteins of Gp1 mGluRs in a group of neurological and psychiatric diseases.

rescuing cognitive defects (Ishii and others 2020). Aguilar-Valles A, Matta-Camacho E, Khoutorsky A, Gkogkas C,
Different from NAMs and PAMs, these molecules do not Nader K, Lacaille JC, and others. 2015. Inhibition of group
always boost or block Gp1 mGluRs in basal condition. I metabotropic glutamate receptors reverses autistic-like
Accordingly, several steps forward have been made with phenotypes caused by deficiency of the translation repressor
eIF4E binding protein 2. J Neurosci 35(31):11125–32.
a long way to go before better understanding the com-
Aguirre JA, Andbjer B, Gonzalez-Baron S, Hansson A,
plete picture.
Stromberg I, Agnati LF, and others. 2001. Group I mGluR
antagonist AIDA protects nigral DA cells from MPTP-
Acknowledgments
induced injury. Neuroreport 12(12):2615–7.
We thank Dr. Iain Bruce for polishing this manuscript and the Albasanz JL, Dalfo E, Ferrer I, Martin M. 2005. Impaired
members of Shen lab for their invaluable feedback on this metabotropic glutamate receptor/phospholipase C signal-
article. ing pathway in the cerebral cortex in Alzheimer’s disease
and dementia with Lewy bodies correlates with stage
Declaration of Conflicting Interests of Alzheimer’s-disease-related changes. Neurobiol Dis
The author(s) declared no potential conflicts of interest with 20(3):685–93.
respect to the research, authorship, and/or publication of this Alvarez FJ, Villalba RM, Carr PA, Grandes P, Somohano PM.
article. 2000. Differential distribution of metabotropic glutamate
receptors 1a, 1b, and 5 in the rat spinal cord. J Comp
Funding Neurol 422(3):464–87.
Amalric M. 2015. Targeting metabotropic glutamate receptors
The author(s) disclosed receipt of the following financial sup- (mGluRs) in Parkinson’s disease. Curr Opin Pharmacol
port for the research, authorship, and/or publication of this arti- 20:29–34.
cle: This work was supported by grants from the National Ambrosi G, Armentero MT, Levandis G, Bramanti P, Nappi G,
Natural Science Foundation of China (81971874, 81625006, Blandini F. 2010. Effects of early and delayed treatment
31970923, and 31820103005). with an mGluR5 antagonist on motor impairment, nigros-
triatal damage and neuroinflammation in a rodent model of
ORCID iDs Parkinson’s disease. Brain Res Bull 82(1–2):29–38.
Li-Da Su https://orcid.org/0000-0002-3970-5193 American Psychiatric Association. 2013. Diagnostic and sta-
tistical manual of mental disorders. 5th edition. American
Ying Shen https://orcid.org/0000-0001-7034-5328 Psychiatric Association Publishing.
Anborgh PH, Godin C, Pampillo M, Dhami GK, Dale LB,
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