Schizophrenia is a devastating neuropsychiatric disorder, affecting about 1.1% of the population over the age of 18. Human and mouse genetic studies have identified several schizophrenia susceptibility genes. Among them, neuregulin-1 (Nrg1), a pleiotropic signaling molecule, is confirmed as a risk gene for schizophrenia (Stefansson et al., 2002;Hall et al., 2006;Law et al., 2006). How functional changes in Nrg1 signaling lead to schizophrenia is an important research topic. Proteolytic cleavage of Nrg1 is required to release a functional fragment that will interact with its cognate receptors of the ErbB family to exert cell-cell signaling (Falls, 2003;Mei and Xiong, 2008). In our studies of BACE1, which was initially discovered as the -secretase for cleaving amyloid precursor protein to release A (Vassar et al., 1999;Yan et al., 1999;Hussain et al., 1999;Sinha et al., 1999;Lin et al., 2000), we have shown that BACE1 cleaves transmembrane Nrg1 to release a secreted EGF-domain- containing N-terminal fragment and to exert a signaling function (Hu et al., 2008;Fleck et al., 2013). Mice with deficiency in BACE1 exhibit altered Nrg1 signaling function and develop schizophrenia-like phenotypes (Savonenko et al., 2008). One intriguing question is whether enhancing Nrg1 activity in BACE1-null mice will ameliorate behaviors. Related to this question, we have recently generated a mouse model which expressed BACE1-cleaved Nrg1 N-terminal fragment (termed as Nrg1-ntf ) under the control of tetracycline (Tet) responsible element (Tet-Off promoter). We found that overexpression of Nrg1-ntf in transgenic mice (Tg- N1 /T mice) enhances Nrg1 signaling activity, as its downstream signaling molecules Akt and Erk are activated. However, contrary to our expectations, our functional study shows that Tg-N1 /T mice develop schizophrenia- like behaviors, which can be reversed if transgene expression is switched off. Results from our lab and others imply that abnormally hypo- or hyper-functional Nrg1 can lead to schizophrenia. Since the dys-regulated expression of schizophrenia susceptibility genes may affect normal brain development and lead to the gradual appearance of different symptoms at different ages (Piper et al., 2012;Powell, 2010;Rapoport et al., 2005), we aim to test our hypothesis that increased Nrg1 activity during early development, but not during adulthood, contributes to subsequent schizophrenia-like behaviors in the adult. To test our hypothesis in this study, we propose two specific aims.
Aim 1 : To determine whether increased Nrg1 activity in the adult has an impact on schizophrenia-like behaviors.
Aim 2 : To explore molecular mechanisms associated with schizophrenia-like behaviors in N1 /T transgenic mice.

Public Health Relevance

Schizophrenia is a devastating neuropsychiatric disorder, which affects about 1.1% of the population over the age of 18. About 100,000 new patients in the US (1.5 million worldwide) are diagnosed with schizophrenia each year, and a total of 2.7 million US citizens over the course of their lives suffer from this disease. Patients with schizophrenia should be better treated to regain their quality of life, and early diagnosis, intervention and early use of new medications can lead to better clinical outcomes. This study aims to investigate origin of genetic cause of schizophrenia by focus the study on a newly generated mouse model. In this new model, a transgene derived from a naturally cleaved fragment of neuregulin-1 (Nrg1) by a protease called BACE1 is expressed under the control of tetracycline-inducible promoter, and treatment of mice with doxycycline (more stable form of tetracycline) can temporarily control the expression of this transgene. We have found that mice expressing this transgene develop schizophrenia-like behaviors. This study will investigate what are molecular changes are required for causing this schizophrenia-like phenotypes and when these changes are critical for the pathogenesis. This hypothesis is based on the fact that patients carrying mutated genes do not express schizophrenia symptoms until early adolescence, suggesting latent effects from mutated genes. Identifying these temporally controlled factors as schizophrenia susceptibility genes may aid in developing better therapies for schizophrenia, as current therapies mainly rely on the use of antipsychotic drugs to ameliorate symptom rather than to cure the disease.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH103942-01A1
Application #
8825231
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Nadler, Laurie S
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195