Metabotropic glutamate receptor, mGlu5, mediates enhancements of hippocampal long-term potentiation after environmental enrichment in young and old mice

Buschler, Arne; Manahan‐Vaughan, Denise

doi:10.1016/j.neuropharm.2016.06.003

Cited by 35 publications

(27 citation statements)

References 107 publications

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“…mGluR5 is ubiquitously expressed across several key brain areas, such as the hippocampus, nucleus accumbens, dorsal striatum, and cerebral cortex [36,37]. It also plays a critical role in various forms of synaptic plasticity [1,22,[38][39][40]. These characteristics have suggested mGluR5 as an important therapeutic target for the treatment of various neuropsychiatric and neurodegenerative disorders [41][42][43], with the potential for alleviating problems associated with disruptions across a number of important cognitive domains.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Genetic and pharmacological manipulations targeting metabotropic glutamate receptor 5 (mGluR5) affect performance in behavioural paradigms that depend on cognitive flexibility. Many of these studies involved exposing mice to highly stressful conditions including electric foot shocks or water immersion and forced swimming. Because mGluR5 is also implicated in resilience and stress responses, however, apparent impairments in inhibitory learning may have been an artifact of manipulation-induced changes in affective state. To address this, we present here a characterization of cognitive flexibility in mGluR5 knockout (KO) mice conducted with a rodent touchscreen cognitive assessment apparatus in which the animals experience significantly less stress. Our results indicate a significant reversal learning impairment relative to wild-type (WT) controls in the two-choice Visual Discrimination-Reversal (VDR) paradigm. Upon further analysis, we found that this deficit is primarily driven by a prolonged period of perseveration in the early phase of reversal. We also observed a similar perseveration phenotype in the KO mice in the Extinction (EXT) paradigm. In addition, mGluR5 KO mice show higher breakpoints in the touchscreen Progressive Ratio (PR) and altered decision making in the Effort-related Choice (ERC) tasks. Interestingly, this impairment in PR is an additional manifestation of an increased propensity to perseverate on the emission of relatively simplistic behavioural outputs. Together, these findings suggest that under conditions of low stress, mGluR5 KO mice exhibit a pronounced perseverative phenotype that blunts cognitive flexibility.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…It encodes for the glutamate metabotropic receptor 4, and is a hub gene in consensus module M25, whose genes are downregulated and overrepresented for glutamate receptor signalling 11 . In addition, Grm5 , encoding a receptor of the same protein family, has been linked to HD-like impairments in Hdh(Q111/Q111) mice 48 and implicated in hippocampal effects of environmental enrichment 49 . The observed upregulation of Grm4 in TG EE animals might, thus, be part of known protective responses of EE 23 , and are in line with previously reported findings of metabotropic receptors in neuroprotection 50 .…”

Section: Discussionmentioning

confidence: 99%

Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease

Novati

Hentrich

Wassouf

et al. 2018

Sci Rep

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Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene which results in progressive neurodegeneration in the striatum, cortex, and eventually most brain areas. Despite being a monogenic disorder, environmental factors influence HD characteristics. Both human and mouse studies suggest that mutant HTT (mHTT) leads to gene expression changes that harbor potential to be modulated by the environment. Yet, the underlying mechanisms integrating environmental cues into the gene regulatory program have remained largely unclear. To better understand gene-environment interactions in the context of mHTT, we employed RNA-seq to examine effects of maternal separation (MS) and environmental enrichment (EE) on striatal gene expression during development of BACHD rats. We integrated our results with striatal consensus modules defined on HTT-CAG length and age-dependent co-expression gene networks to relate the environmental factors with disease progression. While mHTT was the main determinant of expression changes, both MS and EE were capable of modulating these disturbances, resulting in distinctive and in several cases opposing effects of MS and EE on consensus modules. This bivalent response to maternal separation and environmental enrichment may aid in explaining their distinct effects observed on disease phenotypes in animal models of HD and related neurodegenerative disorders.

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“…However, it seems probable that later time points or other forms of plasticity may be impeded in the dose range that ameliorated the detrimental effects of Aß. Extensive research has shown that certain forms of LTP, LTD and depotentiation are inhibited by these agents in brain areas including the hippocampus under physiological conditions (Anwyl, 2009;Buschler and Manahan-Vaughan, 2016;Collingridge et al, 2010;Qi et al, 2013;Zarnadze et al, 2016) . Indeed, mGlu5 receptor activation can "reinforce" the induction of longer-lasting forms of LTP, and late-phase LTP may be more sensitive than early phase LTP to block of group I receptors (Balschun et al, 1999;Manahan-Vaughan, 1997).…”

Section: Discussionmentioning

confidence: 99%

Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: Longitudinal studies

Zhang

Klyubin

et al. 2017

Neuropharmacology

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Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches.

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Metabotropic glutamate receptor, mGlu5, mediates enhancements of hippocampal long-term potentiation after environmental enrichment in young and old mice

Cited by 35 publications

References 107 publications

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

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

Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease

Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: Longitudinal studies

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