The role of group II metabotropic glutamate receptors in cognition and anxiety: comparative studies in GRM2(-/-), GRM3(-/-) and GRM2/3(-/-) knockout mice.

Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by GRM2 and GRM3) have been implicated in both cognitive and emotional processes, although their precise role remains to be established. Studies with knockout (KO) mice provide an important approach for investigating the role of specific receptor genes in behaviour. In the present series of experiments we extended our prior characterisation of GRM2/3(-/-) double KO mice and, in complementary experiments, investigated the behavioural phenotype of single GRM2(-/-) and GRM3(-/-) mice.

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.

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.

Hippocampal mossy fiber long-term depression in Grm2/3 double knockout mice.

Group II metabotropic glutamate receptors (mGluR2, encoded by Grm2, and mGluR3, encoded by Grm3) are inhibitory autoreceptors that negatively modulate the adenylate cyclase signaling cascade. Within the hippocampus, mGluR2 is believed to play a key role in the induction of long-term depression (LTD) at mossy fiber-CA3 synapses. Here, we used Grm2/3 double knockout (dko) mice to investigate to what extent group II mGluRs are necessary for mossy fiber LTD.

Altered hippocampal expression of glutamate receptors and transporters in GRM2 and GRM3 knockout mice.

Group II metabotropic glutamate receptors (mGluR2 and mGluR3, also called mGlu2 and mGlu3, encoded by GRM2 and GRM3, respectively) are therapeutic targets for several psychiatric disorders. GRM3 may also be a schizophrenia susceptibility gene. mGluR2-/- and mGluR3-/- mice provide the only unequivocal means to differentiate between these receptors, yet interpretation of in vivo findings may be complicated by secondary effects on expression of other genes.

NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory.

NMDA receptors (NMDARs) containing NR2A (epsilon1) subunits are key contributors to hippocampal long-term potentiation (LTP) induction in adult animals and have therefore been widely implicated in hippocampus-dependent spatial learning. Here we show that mice lacking the NR2A subunit or its C-terminal intracellular domain exhibit impaired spatial working memory (SWM) but normal spatial reference memory (SRM). Both NR2A mutants acquired the SRM version of the water maze task, and the SRM component of the radial maze, as well as controls.

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice.

Stable tubule-only polypeptide (STOP) proteins are a family of microtubule associated proteins (MAPs) important in microtubule stabilization. Data indicating a role for microtubules in synaptic function has come from studies of the STOP null mouse, which exhibits synaptic deficits, in association with behavioural changes that are alleviated by antipsychotic treatment. These findings suggested that STOP mutant mice may be useful in studies of synaptic function, and could be especially relevant to schizophrenia, postulated to be a disorder of the synapse.

Cognitive style in bipolar disorder.

Background: Abnormalities of cognitive style in bipolar disorder are of both clinical and theoretical importance.

Aims: To compare cognitive style in people with affective disorders and in healthy controls.

Method: Self-rated questionnaires were administered to 118 individuals with bipolar I disorder, 265 with unipolar major recurrent depression and 268 healthy controls.