Touchscreen testing reveals clinically relevant cognitive abnormalities in a mouse model of schizophrenia lacking metabotropic glutamate receptor 5

Abstract

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in certain forms of synaptic plasticity and cognitive function. mGlu5 knockout (KO) mice and mGlu5 antagonists have been previously used to study the pathophysiology of schizophrenia as they have been shown respectively to display or induce endophenotypes relevant to schizophrenia. While schizophrenia presents with generalized cognitive impairments, the cognitive phenotype of mice lacking mGlu5 has so far only been explored using largely hippocampal-dependent spatial and contextual memory tasks. To address this, we used a touchscreen system to assess mGlu5 KO mice for pairwise visual discrimination, reversal learning, and extinction of an instrumental response requiring no discrimination. Furthermore, we tested the role of mGlu5 in working memory using the Trial-Unique Non-Matching to Location (TUNL) task utilizing pharmacological ablation. mGlu5 KO mice were impaired on discrimination learning, taking longer to reach criterion and requiring more correction learning trials. Performance on reversal learning was also impaired, with mGlu5 KO mice demonstrating a perseverative phenotype. The mGlu5 KO mice responded at a higher rate during extinction, consistent with this perseverative profile. In contrast, wildtype mice treated acutely with an mGlu5 antagonist (MTEP) showed no deficits in a touchscreen task assessing working memory. The present study demonstrates learning and memory deficits as well as an increased perseverative phenotype following constitutive loss of mGlu5 in this mouse model of schizophrenia. These findings will inform translational approaches using this preclinical model and the pursuit of mGlu5 as therapeutic target for schizophrenia and other brain disorders.

Assessment of mGluR5 KO mice under conditions of low stress using a rodent touchscreen apparatus reveals impaired behavioural flexibility driven by perseverative responses

“…While this paper was in preparation, another group independently reported similar phenotypes of the mGluR5 KO mice in touchscreen-based VDR and EXT cognitive tests [49]. The fact that two independent groups are reporting similar data support the reliability of the observed cognitive phenotypes of mGluR5 KO mice and the high reproducibility of automated touchscreen-based cognitive test methods.…”

Translating the Human CANTAB Touchscreen Based Tasks to Evaluate Learning and Memory in Mouse Models of Down Syndrome

“…The increased number of trials suggests that both Dp(16)1/Yey and Ts1Cje mice exhibit a perseverative behavior, repetitive behavior and/or attention-deficit-hyperactivity disorder. Similar findings were reported for the mGluR5 (metabotropic glutamate receptor 5) knock-out mouse model 37,38 .…”

Paradoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene

“…It is worth noting that those previous touchscreen studies were done using the “Med Associates” boxes, with sugar pellet rewards, whereas our study took place in the newly commercialized chambers (Cambden Instruments) with liquid rewards (i.e., strawberry milk), which may have influenced task difficulty (Horner et al, ; Oomen et al, ). Indeed, in the newly commercialized chambers, our group now routinely performs the Trial‐Unique Non‐Matching to Location task (Zeleznikow‐Johnston et al, ; Zeleznikow‐Johnston et al, ), a task that was deemed too difficult to be performed by mice in the previous generation of chambers (Oomen et al, ). Despite this, overall, our results show that exercise clearly affects cognitive flexibility in SERT HET mice, on both the MWM and the spatial pattern separation touchscreen task.…”