A novel mouse model with neuroligin-2 R215H mutation for the study of psychiatric disorders

Open Access
- Author:
- Jiang, Dongyun
- Graduate Program:
- Molecular, Cellular and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 04, 2016
- Committee Members:
- Gong Chen, Dissertation Advisor/Co-Advisor
Gong Chen, Committee Chair/Co-Chair
Bernhard Luscher, Committee Member
Yingwei Mao, Committee Member
Nanyin Zhang, Outside Member
Aimin Liu, Committee Member - Keywords:
- neuroligin 2
R215H mutation
schizophrenia
psychiatric disorders
GABAergic deficits - Abstract:
- Schizophrenia (SCZ) is a severe mental disorder affecting about 1 percent of world population. This chronic neural developmental disorder persists throughout patients’ life and causes enormous emotional distress and economic burden for family members. Schizophrenia is a highly heritable disorder. Despite decades of research, the etiology and pathophysiology of schizophrenia is still unclear, and the treatment of this disorder is largely depending on the anti-psychosis drugs partially relieving the symptoms but with many side effects. It is important to have a better understanding of the molecular mechanisms of schizophrenia in order to find new treatment for the disease. However, so far there are very limited animal models that can be used to study the mechanisms of schizophrenia and related disorders. GABAergic neural transmission deficits have long been proposed to be an important pathophysiology of schizophrenia. Recent genetic and genomic studies have identified mutations in GABA-related genes in a substantial amount of schizophrenia patients. We have recently reported several mutations in nlgn2, a gene encoding cell adhesion molecule neuroligin 2 (NL-2), in a group of SCZD patients. NL-2 is critical for GABAergic synapse formation and function. Our previous in vitro experiments showed that one of the NL-2 mutations, R215H, is a loss-of-function mutation that failed to support GABAergic synapse formation and function. Here, we introduced the single point mutation R215H into mouse genome and generated the NL-2 R215H knock-in (KI) mouse line. We found that NL-2 R215H KI mice display anxiety like behaviors, impaired pre-pulse inhibition (PPI), working memory deficit, and hypersensitive stress response, partially recapitulating schizophrenia-like symptoms. Functionally, we discovered that NL-2 R215H KI mice have reduced GABAergic synapse development, decreased GABAergic neural transmission, and impaired hippocampal activation toward acute stress. Transcriptomic analyses through RNA-seq revealed a number of genes in the NL-2 R215H KI mice that are susceptible genes in patients with psychiatric disorders including schizophrenia patients. Our studies suggest that these newly generated NL-2 R215H KI mice may be a unique mouse model for the study of SCZD and related psychiatric disorders, in particular those disorders caused by GABAergic deficits. Future studies on this mouse model may provide new insights into the molecular and cellular mechanisms of psychiatric disorders and lead to potential new drug treatment.