Disturbances of novel object exploration and recognition in a chronic ketamine mouse model of schizophrenia.

Abstract

Schizophrenia is a chronic and devastating disease with an overall lifetime risk of 1%. While positive symptoms of schizophrenia such as hallucinations and delusions are reduced by antipsychotic medication based on the inhibition of type 2 dopaminergic receptors (D2R), negative symptoms (e.g. reduced motivation) and cognitive symptoms (e.g. impaired working memory) of schizophrenia are not effectively treated by current medication. This dichotomy might arise in part because of our limited understanding of the pathophysiology of negative and cognitive symptoms in schizophrenia. In addition to genetic approaches, chronic systemic application of NMDA inhibitors such as ketamine have been used to generate rodent models, which displayed several relevant endophenotypes related to negative and cognitive symptoms and might thus facilitate mechanistic studies into the underlying pathophysiology. In this context, previous behavioral testing identified impairments in novel object recognition memory as a key feature in chronic NMDA-inhibitor schizophrenia rodent models. Using a chronic ketamine mouse model, we have however identified are more complex behavioral phenotype including deficits in novel space and novel object exploration in combination deficits in short-term novel object recognition memory. These impairments in novelty discrimination are in line with prefrontal and hippocampal reductions in parvalbumin-expression as well as reduced expression of the early immediate gene c-fos after novel-object exploration in hippocampal areas in our model. Our results indicate that adult C57Bl6N mice chronically treated with ketamine display combined impairments in novelty exploration and recognition, which might represent both motivational (negative) and cognitive symptoms of schizophrenia.