F A C U L T Y P R O F I L E
GOGOS, JOSEPH A., M.D.
Genetics and Animal Models of Complex Psychiatric Disorders
Office: Physicians & Surgeons | 11th floor | Room 451
My laboratory has elucidated the contribution of rare de novo and inherited mutations to the genetic risk of schizophrenia and develops relevant model systems to understand their impact on neural mechanisms and advance neuropsychiatric therapeutics. Some of the questions we try to answer are: What kind and how many different mutations increase the risk for schizophrenia? What kind of failures in neural circuits in our brain underlie these constellation of symptoms we refer to as schizophrenia? Why do neural circuits fail in particular ways and not others when our genetic program is disturbed by disease mutations? Why are conditions such as schizophrenia so frequent? Toward these goals, my laboratory has two interconnected research programs:
i. Genetics of Complex Psychiatric Disorders: Most psychiatric disorders have a strong genetic component and, therefore, our starting point is findings from human genetic approaches. Our genetics program has contributed a series of genetic discoveries especially on the contribution of rare mutations in the genetic architecture of schizophrenia.
ii. Animal Models of Complex Psychiatric Disorders: We are using mouse models of rare, recurrent, large-effect mutations to ask what are the consequences of a genetic lesion associated with mental illness in humans, on brain structure and function of a model organism, starting at the simpler cellular and synaptic levels to the higher-order circuit and behavior levels. Implementation of a range of state-of-the-art approaches to dissect the biological complexity of schizophrenia is the major component of my lab and has contributed a series of recent discoveries.
Crabtree GW, Park AJ, Gordon JA, Gogos JA. 2016 Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade. Cell Rep. 2016 Oct 4;17(2):570-582. doi: 10.1016/j.celrep.2016.09.029.
Tamura M, Mukai J, Gordon JA, Gogos JA. 2016 Developmental Inhibition of Gsk3 Rescues Behavioral and Neurophysiological Deficits in a Mouse Model of Schizophrenia Predisposition. Neuron 89:1100-1109
Piskorowski RA, Nasrallah K, Diamantopoulou A, Mukai J, Hassan SI, Siegelbaum SA, Gogos JA, Chevaleyre V. 2016 Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome. Neuron 89:163-176
Mukai J, Tamura M, Fénelon K, Rosen AM, Spellman TJ, Kang R, MacDermott AB, Karayiorgou M, Gordon JA, Gogos JA. 2015 Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. Neuron 86:680-695.
Takata A, Xu B, Ionita-Laza I, Roos JL, Gogos JA, Karayiorgou M. 2014 Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82:773-780.
Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA. 2013 Derepression of a Neuronal Inhibitor due to miRNA Dysregulation in a Schizophrenia-Related Microdeletion Cell 152(1-2):262-75.
Fénelon K, Xu B, Lai CS, Mukai J, Markx S, Stark KL, Hsu PK, Gan WB, Fischbach GD, Macdermott AB, Karayiorgou M, Gogos JA. 2013 The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion. J Neurosci. 33(37):14825-14839.
Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, Levy S, Gogos JA, Karayiorgou M. 2012 De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet. 44(12):1365-9.
Kvajo M, McKellar H, Drew LJ, Lepagnol-Bestel AM, Xiao L, Levy RJ, Blazeski R, Arguello PA, Lacefield CO, Mason CA, Simonneau M, O'Donnell JM, MacDermott AB, Karayiorgou M, Gogos JA. 2011 Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.Proc Natl Acad Sci U S A. 108(49):E1349-58.
Sigurdsson T, Stark KL, Karayiorgou M, Gogos JA, Gordon JA. 2010 Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464:763-7.
Mukai J, Dhilla A, Drew LJ, Stark KL, Cao L, Macdermott AB, Karayiorgou M, Gogos JA. 2008 Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci. 11:1302-10.
Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. 2008. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 40:880-5.
Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. 2008. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 40:751-60.
Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, Westphal KG, Olivier B, Sulzer D, Pavlidis P, Siegelbaum SA, Karayiorgou M, Gogos JA. 2005. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 8:1586-94
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. 2004. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet. 36:131-7.