Brady Maher, Ph.D.

About

Brady J. Maher, Ph.D. is a Lead Investigator in the Developmental Neurobiology and Functional Genomics division of the Lieber Institute and an Associate Professor in the Department of Psychiatry and Behavioral Sciences and the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine.

Dr. Maher’s research is focused on understanding fundamental mechanisms involved in brain development and brain function with an emphasis on how dysfunction in these mechanisms can result in neurodevelopmental and psychiatric disorders. By focusing on key developmental genes that are associated with psychiatric risk, his research group is both enhancing our primary understanding of brain development while also making significant inroads into identifying pathophysiological mechanisms underlying psychiatric disorders.

A major focus of his lab is to understand the function of Transcription Factor 4 (TCF4) gene. TCF4 is a clinically pleiotropic gene having association with schizophrenia and autism spectrum disorder (ASD). Autosomal dominant mutations in TCF4 result in Pitt Hopkins syndrome, a rare neurodevelopmental disorder with a variety of symptoms including developmental delays, intellectual disability, absent speech, and breathing abnormalities. His group has shown that TCF4 is an activity-dependent transcription factor that is a critical regulator of cortical development. They have shown TCF4 regulates several developmental steps including cell fate specification, neuronal migration, cortical column formation, and neuronal excitability.

Recently, Dr. Maher’s group demonstrated that TCF4 directly regulates oligodendrocyte development and myelination. This work has led to the hypothesis that defects in myelination are a common pathophysiology across the autism spectrum. His research group is now working on genetic and pharmacological approaches to rescue myelination in PTHS models, with the ultimate goal of applying these therapeutic approaches more broadly to ASD.

Research

Dr. Maher’s lab is interested in understanding the cellular and circuit pathophysiology that underlies neurodevelopmental and psychiatric disorders. Recent progress in clinical genetics has led to the identification of genetic variation and genes that are associated with these disorders. However, information about the function of many of these genes during neurodevelopment and in the adult brain is lacking. His group focuses on trying to understand the function of these risk genes by manipulating their expression level in utero during the peak of cortical development. We then use a variety of approaches and technologies to identify resulting phenotypes and molecular mechanisms including cell and molecular biology, optogenetics, imaging, and electrophysiology.

Current projects in the lab are focused on understanding the function of transcription factor 4 (TCF4), a clinically pleiotropic gene. Genome-wide association studies have identified genetic variants of TCF4 that are associated with schizophrenia. Autosomal dominant mutations in TCF4 result in Pitt Hopkins syndrome, a rare neurodevelopmental disorder with a variety of symptoms including severe intellectual disability, developmental delays, absent speech, and breathing abnormalities. Using our model system we have identified several interesting electrophysiological and cell biological phenotypes associated with altering the expression of TCF4 in utero. We hypothesize that these phenotypes represent cellular pathophysiology related to these disorders and by understanding the molecular mechanisms responsible for these phenotypes we expect to identify therapeutic targets for drug development.

Selected Publications

Qian, X., Nguyen, H.N., Song, M.M., Hadiono, C., Odgen, S.C., Hammack, C., Yao, B., Hamersky, G.R., Jacob, F., Zhong, C., Yoon, K., Jeang, W., Lin, L., Li, Y., Thakor, J., Berg, D.A., Zhang, C., Kang, E., Chickering, M., Nauen, D., Ho, C., Wen, Z., Christian, K.M., Shi, P., Maher, B.J., Wu, H., Jin, P., Tang, H., Song, H., Ming, G.: Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell (2016) In Press.

Li M., Jaffe A.E., Straub, R.E., Tao, R., Shin, J.H., Wang, Y., Chen, Q., Li, C., Jia, Y., Ohi, K., Maher, B.J., Brandon, N.J., Cross, A., Chenoweth, J., Hoeppner, D.J., Wei, H., Hyde, T.M., McKay, R.D., Kleinman, J.E., Weinberger, D.R.: A Human-specific AS3MT isoform and BORCS7 are Molecular Risk Factors in the 10z24.32 Schizophrenia Locus. Nature Medicine (2016) In Press.

Rannals, M.D., Cerceo-Page, S., Campbell, M., Hamersky G., Briley, A., Gallo, R., Hyde, T.M., Kleinman, J.E., Shin, J.H., Jaffe, A.E., Weinberger, D.R., Maher, B.J.: Psychiatric risk gene Transcription Factor 4 Regulates the Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. Neuron April 6 (2016).

Calcaterra, N., Hoeppner D., Wei H., Jaffe A., Maher B.J.+, Barrow J.+. The Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued Through Proteasome Inhibition for High Throughput Screening. Scientific Reports Feb (2016) +corresponding author

Saito, A., Taniguchi, Y., Rannals, M.D., Merfeld, E.B., Ballinger, M.D., Koga, M., Ohtani, Y., Gurley, D.A., Sedlak, T.W., Cross, A., Moss, S.J., Brandon, N.J., Maher, B.J., Kamiya, A.: Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Molecular Psychiatry Jan 5 (2016).

Jaffe AE, Shin J, Collado-Torres L, Leek JT, Tao R, Li C, Gao Y, Jia Y, Maher BJ, Hyde TM, Kleinman JE, Weinberger DR: Developmental regulation of human cortex transcription and its clinical relevance at single base resolution. Nature Neuroscience 2015; 18(1):154-61; NIHMS642947; PMC4281298.

Tao R, Cousijn H, Jaffe AE, Burnet PW, Edwards F, Eastwood SL, Shin JH, Lane TA, Walker MA, Maher BJ, Weinberger DR, Harrison PJ, Hyde TM, Kleinman JE: Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706. JAMA psychiatry. 2014; 71(10):1112-20; PMC25162540.

Centanni, T.M., Booker A.B, Sloan A.M.,Chen F, Maher B.J.,Carraway, R.S., Khodaparast, N., LoTurco, J.J., Kilgard M.P.: Knockdown of the dyslexia-associated gene KIAA0319 impairs temporal responses to speech stimuli in rat primary auditory cortex. Cerebral Cortex, in press.

Xiaoqin Zhu, Hao Zuo, Brady J. Maher, David R Serwanski, Joseph J. LoTurco, Q. Ricard Lu and Akiko Nisiyama: Olig2-dependent development fate switch of NG2 cells. Development 2012 Jul; 139(13): 2299-307; PMC3367441

Brady J. Maher and Joseph J. LoTurco: Disrupted-in-Schizophrenia (DISC1) functions presynaptically at glutamatergic synapses, PLoS ONE 2012 Mar 30; 7(3):e34053; PMC3316587

Matthew J. Girgenti, Joseph J. LoTurco, and Brady J. Maher: ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2, PLoS ONE 2012 Feb 27; 7(2):e32404; PMC3288100

Brady J. Maher and Joseph J. LoTurco: In Utero Electroporation for Cellular Transgenesis in the Developing Mammalian Forebrain, Neuromethods 2012 Jan 11; 65:113-128.

Brady J. Maher and Gary L. Westbrook: Experience-dependent Maturation of the Glomerular microcircuit, Proceedings of the National Academy of Sciences 2009 Sep 29; 106(39):16865-70; PMC2757847

Brady J. Maher and Joseph J. LoTurco: Stop and Go GABA, Nature Neuroscience 2009 Jul: 12(7): 817-8

Ken R. Tovar, Brady J. Maher and Gary L. Westbrook: Direct Actions of Carbenoxolone on Synaptic Transmission and Neuronal Membrane Properties, Journal of Neurophysiology 2009 Aug: 102(2): 974-8; PMC2724329

Brady J. Maher and Gary L. Westbrook: Co-transmission of Dopamine and GABA in Periglomerular Cells, Journal of Neurophysiology 2008 Mar; 98 (3):1559-64; PMID: 18216231

Brady J. Maher and Gary L. Westbrook: SK Channel Regulation of Dendritic Excitability and Dendrodendritic Inhibition in the Olfactory Bulb, Journal of Neurophysiology 2005 Dec; 94 (6):3743-50; PMID: 16107526

Paul T. Kelly, Roger L. MacKinnon II, Roger Dietz, Brady J. Maher, J. Wang: Postsynaptic IP3 Receptor-mediated Ca2+ Release Modulates Synaptic Transmission in Hippocampal Neurons, Brain Research Molecular Brain Research 2005 Apr 27; 135(1-2):232-48; PMID: 15857686

Brady J. Maher, Roger L. Mac Kinnon II, Jihong Bai, Edwin R. Chapman, and Paul T. Kelly: Activation of Postsynaptic Ca2+ Stores Modulates Glutamate Receptor Cycling in Hippocampal Neurons, Journal of Neurophysiology 2005 Jan; 93(1):178-88; PMID: 15604462

Team Members

Srinidhi R. Sripathy Rao

Alissa Tuttle

Huei-Ying Chen

Brittany Davis

Yanhong Wang

Joseph Bohlen