scholarly journals Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

2017 ◽  
Author(s):  
Stefania Bellini ◽  
Kelsey E. Fleming ◽  
Modhurika De ◽  
John P. McCauley ◽  
Maurice A. Petroccione ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Brain Region ◽  
Glutamate Transporter ◽  
Synaptic Function ◽  
Movement Execution ◽  
Metabotropic Glutamate ◽  
Motor Behaviors ◽  
Group I ◽  
Compulsive Behaviors ◽  
Neuronal Glutamate Transporter

ABSTRACTThere is an ongoing debate on the contribution of the neuronal glutamate transporter EAAC1 to the onset of compulsive behaviors. Here we use behavioral, electrophysiological, molecular and viral approaches in male and female mice to identify the molecular and cellular mechanisms by which EAAC1 controls the execution of repeated motor behaviors. Our findings show that in the striatum, a brain region implicated with movement execution, EAAC1 limits group I metabotropic glutamate receptor (mGluRI) activation, facilitates D1 dopamine receptor (D1R) expression and ensures long-term synaptic plasticity. Blocking mGluRI in slices from mice lacking EAAC1 restores D1R expression and synaptic plasticity. Conversely, activation of intracellular signaling pathways coupled to mGluRI in D1R-expressing striatal neurons of mice expressing EAAC1 leads to reduced D1R expression and increased stereotyped movement execution. These findings identify new molecular mechanisms by which EAAC1 can shape glutamatergic and dopaminergic signals and control repeated movement execution.SIGNIFICANCE STATEMENTGenetic studies implicate Slc1a1, a gene encoding the neuronal glutamate transporter EAAC1, with obsessive-compulsive disorder (OCD). EAAC1 is abundantly expressed in the striatum, a brain region that is hyperactive in OCD. What remains unknown is how EAAC1 shapes synaptic function in the striatum. Our findings show that EAAC1 limits activation of metabotropic glutamate receptors (mGluRI) in the striatum and, by doing so, it promotes D1R expression. Targeted activation of signaling cascades coupled to mGluRI in mice expressing EAAC1 reduces D1R expression and triggers repeated motor behaviors in mice. These findings provide new information on the molecular basis of OCD and suggest new avenues for its treatment.

scholarly journals Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

2022 ◽  
Vol 23 (2) ◽  
pp. 840
Author(s):  
Li-Min Mao ◽  
Alaya Bodepudi ◽  
Xiang-Ping Chu ◽  
John Q. Wang
Keyword(s):  
Synaptic Plasticity ◽  
Protein Interactions ◽  
Metabotropic Glutamate Receptors ◽  
Adaptor Proteins ◽  
Mammalian Brain ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Associated Proteins

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography

US Neurology ◽  
2010 ◽  
Vol 05 (02) ◽  
pp. 21
Author(s):  
Rosario Sanchez-Pernaute ◽  
Anna-Liisa Brownell ◽  
◽  
Keyword(s):  
Positron Emission Tomography ◽  
Synaptic Plasticity ◽  
Metabotropic Glutamate Receptor ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Emission Tomography ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Mglu5 Receptors

Metabotropic glutamate receptors (mGluR)s are G-protein-coupled receptors that function as modulators of synaptic function and glutamate transmission. Post-synaptically localized subtype 5 mGlu5 receptors are co-localized with adenosine A2a, dopamine, and N-methyl-D-aspartate (NMDA) receptors and regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity. Aberrant synaptic plasticity appears to be involved in a number of developmental and degenerative neuropsychiatric disorders, including Parkinson’s disease. Pharmacological modulation of mGluR5 could potentially open new therapeutic avenues for the treatment of such disorders, for both symptomatic and neuroprotective purposes. In this review, we summarize a series ofin vivostudies we performed in order to delineate the anatomical basis and functional role of mGluR5 antagonists in Parkinson’s disease models, taking advantage of high-resolution positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals. Our findings of a prevalent distribution of mGluR5 in the striatum and limbic structures and a significant binding enhancement following dopamine lesions support the role of mGlu5 receptors in modulating dopamine- and glutamate-dependent signaling and synaptic plasticity within the basal ganglia cortico–subcortical loops.

System Identification of mGluR-Dependent Long-Term Depression

2013 ◽  
Vol 25 (3) ◽  
pp. 650-670 ◽  
Author(s):  
Tim Tambuyzer ◽  
Tariq Ahmed ◽  
C. James Taylor ◽  
Daniel Berckmans ◽  
Detlef Balschun ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
System Identification ◽  
Metabotropic Glutamate Receptor ◽  
Synaptic Function ◽  
Long Term Depression ◽  
Metabotropic Glutamate ◽  
Powerful Approach ◽  
Underlying Mechanisms ◽  
First Time

Recent advances have started to uncover the underlying mechanisms of metabotropic glutamate receptor (mGluR)–dependent long-term depression (LTD). However, it is not completely clear how these mechanisms are linked, and it is believed that several crucial mechanisms remain to be revealed. In this study, we investigated whether system identification (SI) methods can be used to gain insight into the mechanisms of synaptic plasticity. SI methods have been shown to be an objective and powerful approach for describing how sensory neurons encode information about stimuli. However, to our knowledge, it is the first time that SI methods have been applied to electrophysiological brain slice recordings of synaptic plasticity responses. The results indicate that the SI approach is a valuable tool for reverse-engineering of mGluR-LTD responses. We suggest that such SI methods can aid in unraveling the complexities of synaptic function.

scholarly journals Role of Spinophilin in Group I Metabotropic Glutamate Receptor Endocytosis, Signaling, and Synaptic Plasticity

2016 ◽  
Vol 291 (34) ◽  
pp. 17602-17615 ◽  
Author(s):  
Andrea R. Di Sebastiano ◽  
Sandra Fahim ◽  
Henry A. Dunn ◽  
Cornelia Walther ◽  
Fabiola M. Ribeiro ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Endocytosis ◽  
Metabotropic Glutamate ◽  
Group I

Astrocytic group I mGluR-dependent potentiation of astrocytic glutamate and potassium uptake

2013 ◽  
Vol 109 (9) ◽  
pp. 2404-2414 ◽  
Author(s):  
Prakash Devaraju ◽  
Min-Yu Sun ◽  
Timothy L. Myers ◽  
Kelli Lauderdale ◽  
Todd A. Fiacco
Keyword(s):  
Charge Transfer ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Uptake ◽  
Hippocampal Slices ◽  
Glutamate Transporter ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group I Mglurs ◽  
G Protein Coupled

One of the most important functions of astrocytes is removal of glutamate released during synaptic transmission. Surprisingly, the mechanisms by which astrocyte glutamate uptake is acutely modulated remain to be clarified. Astrocytes express metabotropic glutamate receptors (mGluRs) and other G protein-coupled receptors (GPCRs), which are activated during neuronal activity. Here, we test the hypothesis that astrocytic group I mGluRs acutely regulate glutamate uptake by astrocytes in situ. This hypothesis was tested in acute mouse hippocampal slices. Activation of astrocytic mGluRs, using a tetanic high-frequency stimulus (HFS) applied to Schaffer collaterals, led to potentiation of the amplitude of the synaptically evoked glutamate transporter currents (STCs) and associated charge transfer without changes in kinetics. Similar potentiation of STCs was not observed in the presence of group I mGluR antagonists or the PKC inhibitor, PKC 19–36, suggesting that HFS-induced potentiation of astrocyte glutamate uptake is astrocytic group I mGluR and PKC dependent. Pharmacological stimulation of a transgenic GPCR (MrgA1R), expressed exclusively in astrocytes, also potentiated STC amplitude and charge transfer, albeit quicker and shorter lasting compared with HFS-induced potentiation. The amplitude of the slow, inward astrocytic current due to potassium (K+) influx was also enhanced following activation of the endogenous mGluRs or the astrocyte-specific MrgA1 Gq GPCRs. Taken together, these findings suggest that astrocytic group I mGluR activation has a synergistic, modulatory effect on the uptake of glutamate and K+.

Facilitation of long-term potentiation by prior activation of metabotropic glutamate receptors

1996 ◽  
Vol 76 (2) ◽  
pp. 953-962 ◽  
Author(s):  
A. S. Cohen ◽  
W. C. Abraham
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Male Rats ◽  
Dependent Manner ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Term Potentiation ◽  
Gabaa Receptor Antagonist

1. The influence of prior metabotropic glutamate receptor (mGluR) activation on subsequent long-term potentiation (LTP) induction was investigated with the use of the mGluR agonist 1-amino-cyclopentane-1S,3R-dicarboxylic acid (ACPD, 20 microM). Field potential recordings were made in the stratum radiatum of CA1 slices taken from young adult male rats and from which CA3 was routinely dissected. Theta burst stimulation (TBS) just above threshold was used to induce LTP. 2. A 10-min bath application of ACPD begun 30 min before the TBS facilitated the induction of LTP in a dose-dependent manner and resulted in an enhanced magnitude and stability of LTP. 3. ACPD did not enhance the degree of LTP induced by strong TBS, suggesting that it acts to lower the threshold for LTP induction but does not raise the ceiling on the amount of inducible LTP. 4. This priming effect by ACPD was stereo specific and lasted between 1 and 3 h. Synaptic stimulation during the ACPD application was not necessary for the enhancement of LTP. Blockade of N-methyl-D-aspartate receptors (NMDARs) during ACPD application also failed to affect the enhancement of LTP. 5. ACPD-induced priming of LTP was antagonized by L-2-amino-3-phosphonopropionic acid, suggesting an involvement of group I mGluRs. 6. ACPD-induced enhancement of LTP was not secondary to long-lasting changes in NMDAR activation or GABAAergic inhibition, because it was unaffected by the addition of picrotoxin, a gamma-aminobutyric acid-A (GABAA) receptor antagonist, and isolated NMDAR-mediated responses did not show a long-lasting enhancement in response to ACPD application. 7. These data demonstrate that activation of mGluRs can initiate persistent yet covert changes in synaptic function that facilitate the stable induction of LTP.

scholarly journals Group I mGluR-regulated translation of the neuronal glutamate transporter, excitatory amino acid carrier 1

2011 ◽  
Vol 117 (5) ◽  
pp. 812-823 ◽  
Author(s):  
John R. Ross ◽  
Hariharasubramanian Ramakrishnan ◽  
Brenda E. Porter ◽  
Michael B. Robinson
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Group I ◽  
Amino Acid Carrier ◽  
Neuronal Glutamate Transporter

scholarly journals Obesity-induced astrocyte dysfunction impairs heterosynaptic plasticity in the orbitofrontal cortex

2020 ◽  
Author(s):  
Benjamin K. Lau ◽  
Ciaran Murphy-Royal ◽  
Manpreet Kaur ◽  
Min Qiao ◽  
Grant R. Gordon ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Orbitofrontal Cortex ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Glutamate Transporter ◽  
Gaba Release ◽  
Nutritional Supplement ◽  
List Type ◽  
Metabotropic Glutamate ◽  
Diet Induced Obesity

SummaryOverconsumption of palatable, energy dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here we show that an impairment of astrocyte glutamate clearance following extended access to a cafeteria diet reduces GABA release onto layer II/III pyramidal neurons in the lateral OFC in rats. This decrease in GABA tone is due to an increase in extrasynaptic glutamate, which activates metabotropic glutamate receptors (mGluR5) and liberates endocannabinoids. In obese rats, these synaptic impairments were rescued by the nutritional supplement, N-acetylcysteine, which restores glutamate homeostasis. Together, our findings indicate that obesity targets astrocytes to disrupt the delicate balance between excitatory and inhibitory transmission in the lateral OFC.HighlightsSynaptic plasticity within the OFC is disrupted with diet-induced obesity.Diet-induced obesity induces hypertrophic astrocytes in the OFC.Failure of astrocytes to clear synaptic glutamate drives endocannabinoid-mediated inhibitory long-term depression of OFC neurons.Astrocytic glutamate transporter function is restored with NAC, which rescues synaptic plasticity.

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