Caveolin-1 regulation of disrupted-in-schizophrenia-1 as a potential therapeutic target for schizophrenia.
Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-in-schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (Hodgkinson et al. 2004; Millar et al. 2000; St Clair et al. 1990) implicated in neuronal development, brain maturation, and neuroplasticity (Brandon and Sawa 2011; Chubb et al. 2008). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. In this study we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Overexpressing Cav-1 specifically in neurons using a neuron-specific synapsin promoter (SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin 1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 coimmunoprecipitated with DISC1 in brain tissue. These findings suggest an important role by which neuron-targeted Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia.



The present study is the first to demonstrate that caveolin-1 can regulate DISC1 expression in neuronal models. Furthermore, the findings are consistent across three separate neuronal models that include rodent neurons (in vitro and in vivo) and human differentiated neurons derived from induced pluripotent stem cells. These findings justify further investigation regarding the modulatory role by caveolin on synaptic function and as a potential therapeutic target for the treatment of schizophrenia.
Department of Anesthesiology, University of California San Diego, La Jolla, California.|VA San Diego Healthcare System, San Diego, California.|Department of Psychiatry and the Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, California.
Adam
A
Kassan
VA San Diego Healthcare System, San Diego, California.
Junji
J
Egawa
VA San Diego Healthcare System, San Diego, California.
Zheng
Z
Zhang
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California; and.
Angels
A
Almenar-Queralt
VA San Diego Healthcare System, San Diego, California.
Quynh My
QM
Nguyen
VA San Diego Healthcare System, San Diego, California.
Yasaman
Y
Lajevardi
VA San Diego Healthcare System, San Diego, California.
Kaitlyn
K
Kim
VA San Diego Healthcare System, San Diego, California.
Edmund
E
Posadas
Department of Psychiatry and the Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, California.
Dilip V
DV
Jeste
Department of Anesthesiology, University of California San Diego, La Jolla, California.|VA San Diego Healthcare System, San Diego, California.
David M
DM
Roth
Department of Anesthesiology, University of California San Diego, La Jolla, California.|VA San Diego Healthcare System, San Diego, California.
Piyush M
PM
Patel
Department of Anesthesiology, University of California San Diego, La Jolla, California.|VA San Diego Healthcare System, San Diego, California.
Hemal H
HH
Patel
Department of Anesthesiology, University of California San Diego, La Jolla, California; bhead@ucsd.edu.|VA San Diego Healthcare System, San Diego, California.|Sanford Consortium for Regenerative Medicine, La Jolla, California.
Brian P
BP
Head
D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D013569:Synapses / Q000378:metabolism; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D000097573:Red Fluorescent Protein
D051242:Caveolin 1; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D016704:Synapsins; D000097573:Red Fluorescent Protein; C495541:Cav1 protein, mouse; C498794:Disc1 protein, mouse
caveolin-1; disrupted-in-schizophrenia-1; schizophrenia; stereotactic injection; synaptic plasticity; synaptic proteins