The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice

Abstract

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1 À/À mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1 À/À mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.

Hippocampal–prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1

“…They show robust, yet selective, impairments in tasks that rely on hippocampus-dependent short-term memory 22–24 , whereas general spatial processing, long-term habituation, and long-term associative learning are left intact 24–26 . For example, Gria1- knockout mice lack spatial working memory, even after extensive training 24,27 . They also display chance level performance in the spatial novelty preference (SNP) Y-maze test 26 , and show pronounced and sustained novelty-induced locomotor hyperactivity 20,27–29 .…”

The role of glutamate receptors in attention‐deficit/hyperactivity disorder: From physiology to disease

“…Besides, hyperactivity produced by a low dose of MK‐801 (NMDA receptor antagonist) is dependent upon dopamine D3 receptor stimulation (Leriche, Schwartz, & Sokoloff, ). D2 receptor antagonist reduce the locomotor hyperactivity of Gria1 −/− mice into a level that was similar to controls (Boerner et al, ). Stimulation of Group II mGluRs contribute to the regulation of motor behavior in the nucleus accumbens and this increased activity requires the activation of both D1 and D2 DA receptors (Breysse, Risterucci, & Amalric, ).…”

“…Gria1 −/− mice exhibited locomotor hyperactivity (Bannerman et al, ; Wiedholz et al, ), which was reduced by Group II mGluR agonists and dopamine D2 receptor antagonist into a level that was similar to controls (Boerner et al, ). Novelty‐ and stress‐induced locomotor hyperactivity of GluR1 KO mice (Cowen et al, ; Fitzgerald et al, ) was decreased by AMPA receptor antagonists, mGluR2/3 agonist, and mood‐stabilizers (Maksimovic, Aitta‐aho, & Korpi, ; Maksimovic, Vekovischeva, Aitta‐aho, & Korpi, ; Procaccini et al, , ).…”

“…The mGluR2/3 antagonist LY341495 normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels (Vengeliene et al, ). AMPARs antagonists, mGluR7 agonist, Group II mGluR agonists, and dopamine D2 receptor antagonist attenuated locomotor hyperactivity and novelty‐induced hyperlocomotion of the GluRs knockout mice (Boerner et al, ; Maksimovic, Aitta‐aho, & Korpi, ; Palucha et al, ; Procaccini et al, , ).…”

Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors

“…To further validate our SEP-GluA1 knockin line, we conducted a battery of behavioral experiments using homozygous SEP-GluA1 mice (9 females and 7 males) and WT (9 females and 9 males) littermates (aged 6-10 weeks), as GluA1 knockout mice show deficits in several behaviors, including locomotor activity, anxiety, and spatial memory (Bannerman et al, 2004;Boerner et al, 2017;Bygrave et al, 2019;Sanderson et al, 2007). We assessed locomotor activity by placing animals in an open arena and measuring the number of beam breaks during a 30-minute session.…”