Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning

Abstract

Storage and processing of information at the synaptic level is enabled by the ability of synapses to persistently alter their efficacy. This phenomenon, known as synaptic plasticity, is believed to underlie multiple forms of long-term memory in the mammalian brain. It has become apparent that the metabotropic glutamate (mGlu) receptor is critically required for both persistent forms of memory and persistent synaptic plasticity. Persistent forms of synaptic plasticity comprise long-term potentiation (LTP) and long-term depression (LTD) that last at least for 4 h but can be followed in vivo for days and weeks. These types of plasticity are believed to be analogous to forms of memory that persist for similar time-spans. The mGlu receptors are delineated into three distinct groups based on their G-protein coupling and agonist affinity and also exercise distinct roles in the way they regulate both long-term plasticity and long-term hippocampus-dependent memory. Here, the mGlu receptors will be reviewed both in general, and in the particular context of their role in persistent (>4 h) forms of hippocampus-dependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

“…For example, mGluR5 has important roles in two opposing forms of synaptic plasticity in the hippocampus. These include the long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength, each of which is induced by highly specific patterns of activity of glutamatergic afferents 139 . When mGluR5 is activated by glutamate that is released from the terminals of afferents that fire with low frequency, it induces LTD (or a weakening of synaptic connections).…”

Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents

“…Based on the results from our study, repeated dosing with CDPPB shows significant enhancement of performance in the T-maze, suggesting that subtle changes in receptor density may not affect learning. Spatial learning in rodents is strongly correlated to hippocampal synaptic plasticity and mGlu5 receptors play a critical role in multiple forms of synaptic plasticity both in vitro and in vivo (reviewed by Mukherjee & Manahan-Vaughan, 2012). Interestingly, mGlu5 receptor PAMs are able to enhance both LTP and LTD in the hippocampus (Ayala et al, 2009).…”

Group III Metabotropic Glutamate Receptors: Pharmacology, Physiology and Therapeutic Potential

“…Group III mGlu receptors are thought to be involved in a number of short-and long-term forms of synaptic plasticity within the hippocampus and dentate gyrus, and are most frequently associated with long-term depression (LTD) [199,200]. Thus, a key study by Pelkey et al [149] in 2005 revealed that HFS, or application of high concentrations of L-AP4, induces a form of LTD at mossy fiber-CA3 interneuron synapses that is mGlu7-dependent.…”