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.
Highlights
The metabotropic glutamate receptor 5 is an excitatory post-synaptic receptor localized largely at the periphery of the active zone, where it regulates both ionotropic receptor activity and intracellular processes via G protein-linked second messenger pathways1–3. mGlu[5] receptors are found in brain regions important for cognition, including the hippocampus, striatum, and cortex[4] and are proposed to regulate many cognitive domains and behaviours, including spatial learning, drug discrimination learning, extinction and sensorimotor gating[5–8]
Investigating this mouse model in a touch-screen system for the first time, we demonstrate that mGlu[5] KO mice have robust impairments across discrimination learning and reversal learning, as well as altered responding in extinction
We show that pharmacological disruption of mGlu[5] does not affect working memory
Summary
The metabotropic glutamate receptor 5 (mGlu5) is an excitatory post-synaptic receptor localized largely at the periphery of the active zone, where it regulates both ionotropic receptor activity and intracellular processes via G protein-linked second messenger pathways1–3. mGlu[5] receptors are found in brain regions important for cognition, including the hippocampus, striatum, and cortex[4] and are proposed to regulate many cognitive domains and behaviours, including spatial learning, drug discrimination learning, extinction and sensorimotor gating[5–8]. NMDA receptor antagonists induce schizophrenia-like cognitive deficits in healthy humans and rodents, including impaired cognitive flexibility[12]. Given their effects on glutamatergic signalling, and on NMDA receptor activity, mGlu[5] modulators are promising agents for treatment of psychiatric disorders, the currently untreatable cognitive symptoms. A subset of these behavioural deficits are responsive to treatment with the clinically effective antipsychotic clozapine, supporting the predictive validity of mGlu[5] KO mice in modelling schizophrenia-like behaviours[27] Both KO mice and antagonist-treated mice are used to model and explore the role of mGlu[5] in cognition in health and disease. Cognitive impairments in schizophrenia and other psychiatric disorders are not constrained to long-term or contextual memory, yet the cognitive phenotype of mGlu5-disrupted mice has so far been explored using largely hippocampal-dependent spatial and contextual memory tasks. We hypothesized that in all cases, mGlu[5] disruption would induce broad deficits across all task parameters
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