Acute inhibition of mGluR5 disrupts behavioral flexibility

Abstract

Conditioned cues can sometimes elicit maladaptive responses as seen in the post-traumatic stress disorder (PTSD). Lack of effective fear extinction, which involves a process of inhibitory learning, is hypothesized to associate with PTSD. In this study, we tested the effect of acute pharmacological inhibition of mGluR5 activity on the extinction of fear memory and spatial memory. Intraperitoneal injection of the mGluR5 (metabotropic glutamate receptor 5) antagonist MPEP [2-Methyl-6- (phenylethynyl) pyridine hydrochloride] allowed the retrieval but prevented the extinction of contextual fear memory in mice. Without altering locomotor activity, MPEP inhibited the acquisition but not the consolidation of contextual fear memory. Further, administration of MPEP blocked the extinction of spatial memory in the Morris water maze paradigm. Our data suggest a necessary role of mGluR5 in regulating certain aspects of behavioral flexibility.

In vivo evidence for dysregulation of mGluR5 as a biomarker of suicidal ideation

“…The metabotropic glutamate receptor type 5 (mGluR5) has emerged as a target of interest for PTSD and suicide research. mGluR5 is implicated in mood and anxiety symptoms in both human (3,4) and animal studies (5,6). We recently reported significantly higher mGluR5 availability in individuals with PTSD relative to matched controls across many brain regions (4).…”

The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats.

“…mGlu5 receptors regulate bidirectional synaptic plasticity in fear associated brain regions such as the mPFC and BLA (Niswender & Conn, 2010). Pharmacological and genetic inhibition of mGlu5 function impairs extinction of both cues and contexts paired with footshock in rodents (Sethna & Wang, 2016;Fontanez-Nuin, 2010;Sepulveda-Orengo et al, 2013;Xu et al, 2009), while administration of of mGlu5 positive allosteric modulators (PAM) enhances extinction of footshock-associated contexts (e.g. Sethna & Wang, 2014).…”

“…To explore the neurobiology underlying this effect, brain tissue was collected after the third extinction session and expression of Fos was analyzed in PL, IL, and BLA regions. Given the involvement of PL, IL, and BLA neuronal activity in extinction to conditioned footshock (Cho et al, 2013), and evidence indicating an important role for mGlu5 (Sethna & Wang, 2016), we hypothesized that treatment with CDPPB would result in greater Fos in all three regions. We also expected that due to the opposing influences of the PL and IL neuronal activity during extinction (Vidal-Gonzalez et al, 2006), Fos expression across mPFC regions would be predictive of fear extinction performance.…”

Assessment of mGluR5 KO mice under conditions of low stress using a rodent touchscreen apparatus reveals impaired behavioural flexibility driven by perseverative responses

“…Behavioural flexibility is a key cognitive ability required for effectively addressing the demands of a constantly changing environment. The mGluR5 subtype of metabotropic glutamate receptors is involved in this cognitive function [1][2][3][4]. The studies characterizing this relationship have assessed rodents in which mGluR5 receptor expression or function has been manipulated with genetic or pharmacological tools in reversal learning or extinction paradigms.…”

“…The studies characterizing this relationship have assessed rodents in which mGluR5 receptor expression or function has been manipulated with genetic or pharmacological tools in reversal learning or extinction paradigms. Notably, their behaviours were measured in every study under high stress conditions, for example, using classical (Pavlovian) fear conditioning or water maze escape paradigms [1][2][3][4][5].…”