GluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Mol Psychiatry

Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Molecular Psychiatry (Impact Factor: 14.5). 09/2007; 13(10):970-9. DOI: 10.1038/
Source: PubMed


Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders.

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    • "mGluR7 is a member of the most evolutionarily conserved group III mGluRs and plays a key role in brain and synaptic function. Studies from mGluR7-deficient and siRNA knockdown animals displayed deficits in fear learning, aversive behavior, stress response, and working memory, supporting the key role in brain physiology [Masugi et al., 1999; Cryan et al., 2003; Callaerts-Vegh et al., 2006; Fendt et al., 2008; O'Connor et al., 2012; Fendt et al., 2013]. At the synaptic level, it appears to modulate presynaptic neurotransmitter of Gamma Amino Acid Butyric Acid (GABA) and L-glutamate as well as postsynaptic N-methyl-D-aspartic acid receptors (NMDARs), thereby contributing to different emotional status such as anxiety, depression, and cognitive dysfunction [O'Connor et al., 2010; Nicoletti et al., 2011; Gee et al., 2014]. "
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    ABSTRACT: GRM7, the gene encoding metabotropic glutamate receptor 7 (mGluR7), have been implicated in multiple neuropsychiatric disorders and shown to mediate excitatory synaptic neurotransmitter signaling and plasticity in the mammalian brain. Here we report a 303 kb de novo deletion at band 3q26.1, disrupting five coding exons of GRM7 in a proband with autism spectrum disorder, and hyperactivity. Our exon transcriptome-mutation contingency index method shows that three of the exons within the breakpoint boundaries are under purifying selection and highly expressed in prenatal brain regions. Based on our results and a thorough review of the literature, we propose that haploinsufficiency of the GRM7 product (mGluR7) contributes to autism spectrum disorders and hyperactivity phenotype as seen in the patient described here. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2015; 168(4). DOI:10.1002/ajmg.b.32306 · 3.42 Impact Factor
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    • "istration are described ( Bahi et al . , 2012 ; Cleva et al . , 2012 ) . Activation of mGlu 7 receptors in the amygdala and the periaqueductal gray by AMN082 augments nocicep - tive behavior ( Marabese et al . , 2007 ) . Furthermore , AMN082 prevented the acquisition of fear learning , facilitated fear extinction and impaired LTP in the amygdala ( Fendt et al . , 2008 ) . Interestingly , unlike MAP4 , MPPG and MSOP , MMPIP ( a selective receptor mGlu 7 antagonist ) did not show proconvulsant activity in rodents ( Flor & Acher , 2012 ) . 2 . 3 . 5 . 5 . mGlu 7 receptors and drugs of abuse . Very recent animal findings point a specific influence of tonic activation of mGlu 7 receptors in drug addiction"
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    ABSTRACT: Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction.
    Pharmacology [?] Therapeutics 12/2013; 142(3). DOI:10.1016/j.pharmthera.2013.12.012 · 9.72 Impact Factor
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    • "This dose of DMSO is not known to produce toxic effects [52]. The AMN082 doses were based on previous studies using AMN082 effectively in amygdala-dependent associative learning tasks [36] "
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    ABSTRACT: Metabotropic glutamate (mGlu) receptors impact learning and memory. Although some evidence indicates the importance of these receptors in conditioned taste aversion (CTA), the subtype-specific involvement of mGlu receptors in this associative learning task remains to be determined. These experiments examined the effects of (1R,4R,5S,6R)-4-Amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a selective group II mGlu receptor agonist, cis-2-[[(3,5-Dichlorophenyl)amino]carbonyl] cyclohexanecarboxylic acid (VU0155041), a mGlu4 positive allosteric modulator, N,N'-Dibenzhydrylethane-1,2-diamine (AMN082), a mGlu7 allosteric agonist, and 6-(4-Methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), a mGlu7 negative allosteric modulator, on the acquisition of CTA using male Spraque-Dawley rats. Systemic injections of LY379268, AMN082, and MMPIP prior to conditioning decreased the acquisition of CTA, revealing that mGlu2/3 and mGlu7 are involved in CTA learning.
    Behavioural brain research 07/2013; 253. DOI:10.1016/j.bbr.2013.06.032 · 3.03 Impact Factor
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