Metabotropic Glutamate Receptors as Therapeutic Targets for Cognitive Disorders

Abstract

Since more than one decade, metabotropic glutamate receptors have been under investigation as targets for various CNS disorders such as anxiety, pain, depression, schizpohrenia, Alzheimer's disease and Parkinson's disease. It has been shown that some mGluRs play a crucial role in cognitive processes such as learning and memory, which was initially, demonstrated using knockout mice for each receptor subtype. Later, selective pharmacological tools were developed allowing more specific examinations of the involvement of mGluR1-8 in various forms of learning and memory. Ligands for group I and II mGluRs have been proposed as promising candidates for the treatment of cognitive disorders such as schizophrenia, Fragile X syndrome, Alzheimer's and Parkinson's disease and post traumatic stress disorder, of which some have made it to clinical testing. The present paper reviews relevant data on the role of mGluRs in learning and cognition processes focusing on their utility as targets for cognition enhancement in several CNS diseases.

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

“…Similar results were obtained when animals were treated with mGluR1 antagonists [91]. These results have lead to the conclusions that mGluR1 antagonists induce learning impairment whereas mGluR1 agonists may have therapeutic potential as cognitive enhancers [19]. mGluR5 antagonists dose-dependently impair rodent performance in tests of learning and memory [92,93].…”

“…mGluRs are a family of G-protein coupled receptors that induce slower excitatory synaptic responses than ionotropic receptors, due to the involvement of second messenger signaling cascades in mGluRs [19]. mGluRs form a family of eight receptor subtypes that are divided into 3 groups based on their sequence homologies and second messenger profiles: Group I (mGluR 1 and 5) that are coupled to phospholipase C, Group II (mGluR 2 and 3) that are negatively coupled to adenylyl cyclase, and Group III (mGluR 4, 6, 7, and 8) that are also negatively coupled to adenylyl cyclase [20].…”

“…However, many of the actions of kainate receptors are bidirectional and dependent on experimental conditions, making the receptors difficult to target and function difficult to pinpoint [87]. mGluRs, like ionotropic receptors, contribute to synaptic plasticity required for learning and memory, and the development of agonists specific for each receptor subtype have greatly improved our understanding of the functions of each receptor [19]. Group I mGluR (mGluR1 and mGluR5) activation has been implicated in facilitating cognition.…”

mGluR1/TRPC3-mediated Synaptic Transmission and Calcium Signaling in Mammalian Central Neurons

“…In the mammalian central nervous system, mGluR1 is involved in a variety of physiological functions including memory, cognition, the sensation of pain and fear (Gravius et al 2010). An extensively studied function of the…”

Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5

“…It is therefore possible that one target for the antinociceptive actions of basimglurant in formalin pain and in the model of cold allodynia can be the mGlu5--MOR heteroreceptor complexes [5]. 9.3.1 Basimglurant and learning and memory mGlu5 NAMs such as MPEP interferes with fear conditioning [81] and impairment of learning was reported with this type of drugs [82]. No data are currently available for basimglurant but will be of interest to obtain, especially in view of the deficits in learning and memory found in animals lacking mGlu5 receptors [83].…”