schizophrenia and cognition
Our laboratory is studying the mechanisms and developing treatments for the cognitive deficits associated with Schizophrenia and other psychiatric conditions. For that purpose we have derived and studied animal models with mutations, such as in the DISC1 gene.
Our studies show that a DISC1 inducible mutation causes cognitive, social, affective, and structural deficits in mice not unlike those seen in patients with DISC mutations. Amazingly, our studies demonstrated that this mutation only needs to be present for less than 24-hours during a critical period of post-natal development for all of these symptoms to be expressed.
Thus, DISC1 mutant mice are helping us to understand psychiatric conditions associated with this gene. We have also carried out studies in mice designed to unravel treatments for the cognitive and affective deficits associated with DISC1 mutations. Surprisingly, these studies indicate that some phenotypes caused by DISC1 mutations are due to disruptions of adult mechanisms. Restricting this mutation to less than 500 neurons in the adult dentate gyrus, in a an otherwise normal brain, can cause a number of profound cognitive and psychiatric phenotypes, demonstrating the importance of this neurodevelopmental gene for adult function. We have targeted these adult mechanisms and have encouraging evidence showing that they can be treated in mice with an FDA approved drug.
Zhou, M, Li, W, Huang, S, Song, J, Kim, J Tian, X, Kang, E Sano, Y, Liu, C, Balaji, J, Wu, S, Zhou, Y, Zhou, Y, Parivash, S, Ehninger, D, He, L. Song, H, 3, Ming, G, Silva AJ mTOR Inhibition Ameliorates Cognitive and Affective Deficits Caused by Disc1 Knockdown Specifically in Adult-Born Dentate Granule Neurons. Neuron 77, 647–654, 2013 (PDF)
Ishizuka, K., Chen, J., Taya, S., Li, W., Millar, J.K., Xu, Y., Clapcote, S.J., Hookway, C., Morita, M., Kamiya, A., et al. (2007). Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Molecular psychiatry 12, 897-899.
Li, W., Zhou, Y., Jentsch, J.D., Brown, R.A., Tian, X., Ehninger, D., Hennah, W., Peltonen, L., Lonnqvist, J., Huttunen, M.O Kaprio, J., Trachtenberg, J. T., Silva, A. J.*, Cannon, T. D.2007). Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A 104, 18280-18285. *corresponding author.(PDF)