mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity

Abstract

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.

Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

“…The first mGlu7-selective allosteric agonist N,NЈ-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) has induced both anxiogenic-like (15,20), as well as anxiolytic-like and antidepressant-like behavioral responses in rodents (13,14,(21)(22)(23). However, the latter effects seem in contradiction with anxiolytic-and antidepressant-like behavioral changes observed in mice lacking mGlu7 or after siRNA-mediated knockdown.…”

“…Learned Fear-The role of mGlu7 in anxiety and stress behavior is well documented (10,12,14,18,22,39). Several studies investigating mGlu7's role in emotional behavior indirectly suggested receptor blockade as a promising approach (9, 18).…”

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

“…The extinction of conditioned fear, blocked with downregulation of GRM7, suggests that some of these CNVs may potentially explain certain comorbidities frequently associated with ADHD. 50,51 Recent investigations of structural variation in autism and schizophrenia have found increased de novo and/or overall variation in diseased individuals, leading to the speculation that these diseases may have a sizable number of possible molecular etiologies. 15,19,21,52,53 To date, this theory is consistent with the general lack of success of genetic association studies in identifying common causative variants in neuropsychiatric disorders, including ADHD.…”

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…As such, dysregulation of mGluR7 has been linked to many psychiatric diseases including depression (Bradley et al, 2011;Cryan et al, 2003), anxiety (Fendt et al, 2008;Mitsukawa et al, 2006), schizophrenia (Bolonna et al, 2001;Ohtsuki et al, 2008) and drug addiction Li et al, 2009Li et al, , 2010. In rodents, results have indicated that the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose dependently inhibits cocaine-induced enhancement of electrical brainstimulation reward and intravenous cocaine self-administration in rats ).…”