title: Fractionation of spatial memory in GRM2/3 (mGlu2/mGlu3) double knockout mice reveals a role for group II metabotropic glutamate receptors at the interface between arousal and cognition.
abstract: Group II metabotropic glutamate receptors (mGluR2 and mGluR3, encoded by GRM2 and GRM3) are implicated in hippocampal function and cognition, and in the pathophysiology and treatment of schizophrenia and other psychiatric disorders. However, pharmacological and behavioral studies with group II mGluR agonists and antagonists have produced complex results. Here, we studied hippocampus-dependent memory in GRM2/3 double knockout (GRM2/3(-/-)) mice in an iterative sequence of experiments. We found that they were impaired on appetitively motivated spatial reference and working memory tasks, and on a spatial novelty preference task that relies on animals' exploratory drive, but were unimpaired on aversively motivated spatial memory paradigms. GRM2/3(-/-) mice also performed normally on an appetitively motivated, non-spatial, visual discrimination task. These results likely reflect an interaction between GRM2/3 genotype and the arousal-inducing properties of the experimental paradigm. The deficit seen on appetitive and exploratory spatial memory tasks may be absent in aversive tasks because the latter induce higher levels of arousal, which rescue spatial learning. Consistent with an altered arousal-cognition relationship in GRM2/3(-/-) mice, injection stress worsened appetitively motivated, spatial working memory in wild-types, but enhanced performance in GRM2/3(-/-) mice. GRM2/3(-/-) mice were also hypoactive in response to amphetamine. This fractionation of hippocampus-dependent memory depending on the appetitive-aversive context is to our knowledge unique, and suggests a role for group II mGluRs at the interface of arousal and cognition. These arousal-dependent effects may explain apparently conflicting data from previous studies, and have translational relevance for the involvement of these receptors in schizophrenia and other disorders.
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: Louisa
authors.initials: L
authors.lastname: Lyon
authors.forename: Philip W J
authors.initials: PW
authors.lastname: Burnet
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
authors.forename: Corrado
authors.initials: C
authors.lastname: Corti
authors.forename: J Nicholas P
authors.initials: JN
authors.lastname: Rawlins
authors.forename: Tracy
authors.initials: T
authors.lastname: Lane
authors.forename: Bianca
authors.initials: B
authors.lastname: De Filippis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
mesh_terms: D000818:Animals; D001143:Arousal / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3