Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent

Neuropharmacology. 2004 Jun;46(7):907-17. doi: 10.1016/j.neuropharm.2004.01.018.


Atrophy of the medial temporal lobes, including the glutamatergic cortical-hippocampal circuitry, is an early event in Alzheimer's disease (AD) and probably contributes to the characteristic short-term mnemonic decline. Pharmacological strategies directly targeted to ameliorating this functional decline may represent a novel approach for the symptomatic treatment of AD. Presynaptic group II metabotropic glutamate receptors (i.e. mGlu2 and mGlu3) exert a powerful modulatory influence on the function of these pathways, in particular the perforant pathway. Using a combination of mGlu2 receptor knockout mice and the group II agonist LY354740, we show that activation of mGlu2 receptors produces a cognitive impairment, i.e. a delay-dependent deficit in delayed matching and non-matching to position, and impaired spatial learning in a Morris water maze. Conversely, a group II antagonist, LY341495, improved acquisition of spatial learning. LY354740 potently reduced field excitatory postsynaptic potentials in hippocampal slices from wild type but not mGlu2 receptor knockout mice. Taken together, these results suggest that activation of mGlu2 receptors evokes a powerful inhibitory effect on hippocampal synaptic transmission and mGlu2 agonists produce a cognitive deficit consistent with this change. Conversely, mGlu2 receptor antagonists may improve certain aspects of cognition and thus represent a novel approach for the symptomatic treatment of AD.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Bridged Bicyclo Compounds / pharmacology
  • Cognition / drug effects*
  • Cognition / physiology
  • Dose-Response Relationship, Drug
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Psychomotor Performance / drug effects*
  • Psychomotor Performance / physiology
  • Rats
  • Reaction Time / drug effects*
  • Reaction Time / physiology
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / physiology
  • Xanthenes / pharmacology


  • Amino Acids
  • Bridged Bicyclo Compounds
  • LY 341495
  • Receptors, Metabotropic Glutamate
  • Xanthenes
  • metabotropic glutamate receptor 2
  • eglumetad