Mechanisms of glutamate receptors hypofunction dependent synaptic transmission impairment in the hippocampus of schizophrenia susceptibility gene Opcml-deficient mouse model

• Published in: Molecular brain 2024-10, Vol.17 (1), p.75-14, Article 75
• Main Authors: Sun, Xiaoxuan, Meng, Hu, Lu, Tianlan, Yue, Weihua, Zhang, Dai, Wang, Lifang, Li, Jun
• Format: Article
• Language: English
• Subjects: Amino acids; AMPA/NMDA ratio; Animals; Brain; Disease Models, Animal; Disease susceptibility; Excitatory Postsynaptic Potentials - drug effects; Genetic aspects; Genetic Predisposition to Disease; Glutamate; Glutamatergic neurotransmission; Glutamic Acid - metabolism; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Intrinsic excitability; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Receptors, Glutamate - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - physiopathology; Synaptic Transmission - drug effects
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-024-01148-9

Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption.