Proteomic Characteristics of the Prefrontal Cortex and Hippocampus in Mice with Chronic Ketamine-Induced Anxiety and Cognitive Impairment.

ABSTRACT

Schizophrenia, a complex psychiatric disorder with diverse symptoms, has been linked to ketamine, known for its N-methyl-D-aspartate (NMDA) receptor antagonistic properties. Understanding the distinct roles and mechanisms of ketamine is crucial, especially regarding its induction of schizophrenia-like symptoms. Recent research highlights the impact of ketamine on key brain regions associated with schizophrenia, specifically the prefrontal cortex (PFC) and hippocampus (Hip). This study focused on these regions to explore proteomic changes related to anxiety and cognitive impairment in a chronic ketamine-induced mouse model of schizophrenia. After twelve consecutive days of ketamine administration, brain tissues from these regions were dissected and analyzed. Using tandem mass tag (TMT) labeling quantitative proteomics techniques, 34,797 and 46,740 peptides were identified in PFC and Hip, corresponding to 5,668 and 6,463 proteins, respectively. In the PFC, a total of 113 proteins showed differential expression, primarily associated with the immuno-inflammatory process, calmodulin, postsynaptic density protein, and mitochondrial function. In the Hip, 129 differentially expressed proteins were screened, mainly related to synaptic plasticity proteins and mitochondrial respiratory chain complex-associated proteins. Additionally, we investigated key proteins within the glutamatergic synapse pathway and observed decreased expression levels of phosphorylated CaMKII and CREB. Overall, the study unveiled a significant proteomic signature in the chronic ketamine-induced schizophrenia mouse model, characterized by anxiety and cognitive impairment in both the PFC and Hip, and this comprehensive proteomic dataset may not only enhance our understanding of the molecular mechanisms underlying ketamine-related mental disorders but also offer valuable insights for future disease treatments.