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Brady J. Maher
Brady J. Maher
Department of Psychiatry and Behavioral Sciences
855 N. Wolfe Street
Baltimore, MD 21205
Molecular and physiological basis of psychiatric disorders
My 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. My 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.
Page SC, Hamersky GR, Gallo RA, Rannals MD, Calcaterra NE, Campbell MN, Mayfield B, Briley A, Phan BN, Jaffe AE, Maher BJ. The schizophrenia and autism associated gene, Transcription Factor 4 (TCF4) regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner. Molecular Psychiatry 2017 (in press).
Rannals MD, Page SC, Campbell MN, Gallo RA, Mayfield B, Maher BJ. Neurodevelopmental Models of Transcription Factor 4 Deficiency Converge on a Common Ion Channel as a Potential Therapeutic Target for Pitt Hopkins Syndrome. Rare Diseases Aug 5 (2016).
Qian X, Nguyen HN, Song MM, Hadiono C, Odgen SC, Hammack C, Yao B, Hamersky GR, Jacob F, Zhong C, Yoon K, Jeang W, Lin L, Li Y, Thakor J, Berg DA, Zhang C, Kang E, Chickering M, Nauen D, Ho C, Wen Z, Christian KM, Shi P, Maher BJ, Wu H, Jin P, Tang H, Song H, Ming G. Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell May 19 (2016).
Li M, Jaffe AE, Straub RE, Tao R, Shin JH, Wang Y, Chen Q, Li C, Jia Y, Ohi K, Maher BJ, Brandon NJ, Cross A, Chenoweth J, Hoeppner DJ, Wei H, Hyde TM, McKay RD, Kleinman JE, Weinberger DR. A Human-specific AS3MT isoform and BORCS7 are Molecular Risk Factors in the 10z24.32 Schizophrenia Locus. Nature Medicine June 22 (2016).
Rannals MD, Cerceo-Page, S, Campbell M, Hamersky G, Briley A, Gallo R, Hyde TM, Kleinman JE, Shin JH, Jaffe AE, Weinberger DR, Maher BJ. 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 BJ+, 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 MD, Merfeld EB, Ballinger MD, Koga M, Ohtani Y, Gurley DA, Sedlak TW, Cross A, Moss SJ, Brandon NJ, Maher BJ, 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 Dec 15 (2014).
Maher BJ and LoTurco JJ. Disrupted-in-Schizophrenia (DISC1) functions presynaptically at glutamatergic synapses. PLoS One. 2012; 7(3): e34053. Maher BJ, McGinley MJ and Westbrook GL. Experience-dependent maturation of the glomerular microcircuit. PNAS.2009; 106: 16865-16870.
Maher BJ, McGinley MJ and Westbrook GL. Experience-dependent maturation of the glomerular microcircuit. PNAS.2009; 106: 16865-16870.