Changes in mGlu5 Receptor Signaling Are Associated with Associative Learning and Memory Extinction in Mice

Abstract

Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) naive mice; (ii) control mice exposed to the same environment as learner mice; (iii) leaner mice, trained for four days in a water maze; (iv) mice in which memory extinction was induced by six trials without the platform; (v) mice that spontaneously lost memory. The mGlu5 receptor-mediated PI hydrolysis was significantly reduced in the dorsal hippocampus of learner mice as compared to naive and control mice. The mGlu5 receptor signaling was also reduced in the ventral hippocampus and prefrontal cortex of learner mice, but only with respect to naive mice. Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with increases in mGlu5 receptor and phospholipase-Cβ protein levels in the ventral and dorsal hippocampus, respectively. These findings support a role for mGlu5 receptors in mechanisms underlying spatial learning and suggest that mGlu5 receptors are candidate drug targets for disorders in which cognitive functions are impaired or aversive memories are inappropriately retained.

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

“…Differential activation of these pathways by different ligands has been previously observed in group 1 mGlu receptors and the therapeutic consequences of this must be considered [ 93 , 94 ]. mGlu5 receptor signalling bias has also been linked to particular cognitive effects, with spontaneous memory loss associated with PFC mGlu5 receptor signalling bias towards a PI-independent pathway [ 95 ]. Here, we show that the effects of both VU0409551 and VU0360172 are at least partly mediated by PLC activation, which induces downstream calcium mobilisation.…”

mGluR1/IP3/ERK signaling pathway regulates vestibular compensation in ON UBCs of the cerebellar flocculus

“…31 In addition, our study indicated that VC might be associated with alterations in the phosphoinositide (PI) and p-ERK1/2 pathways mediated by mGluR1α. Teleuca et al 32 utilized in vivo techniques to evaluate PI levels and investigated potential impairments in spatial learning and memory. Their primary objective was to examine the influence of changes in mGluR1 signaling on the PI pathway, as well as the MAP kinase and phosphatidylinositol-3-kinase pathways, in the hippocampus and prefrontal cortex.…”

Role of mGlu5 in Persistent Forms of Hippocampal Synaptic Plasticity and the Encoding of Spatial Experience

“…Metabotropic glutamate (mGlu) receptors comprise a family of G-protein coupled receptors that are present throughout the brain [ 1 , 2 ] and are highly expressed in the hippocampus [ 2 ]. They are specifically involved in the regulation of persistent (>24 h) forms of hippocampal synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) [ 3 , 4 , 5 , 6 , 7 , 8 ], hippocampus-dependent learning [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ].They also support hippocampal information transfer by means of neuronal oscillations [ 16 , 17 ] and the beneficial effects of environmental enrichment on hippocampal function [ 18 ].…”