Hui-Chen Lu, Ph.D.
Hui-Chen Lu, Ph.D.
The Cain Foundation Laboratories
The Jan and Dan Duncan Neurological Research Institute
1250 Moursund St. Suite 1225
Houston, TX 77030
Ph.D. - Baylor College of Medicine
Post-Doctorate - Baylor College of Medicine
My primary research interests are to elucidate the signaling cascades that establish neural circuit connections during brain development, to understand how sensory experiences affect neural circuit wiring and cognitive behaviors, and to identify novel factors required to maintain the health of neural circuits during aging. These interests spanning an organism’s entire life are driven by a growing appreciation that mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism and schizophrenia, while during adult life deteriorating neural networks lead to cognitive decline and dementia. A genetic dissection of the role of mGluR5 signaling in neural circuits and behaviors.
The metabotropic glutamate receptor 5 (mGluR5) is a group 1 metabotropic glutamate receptor that signals via G proteins to activate multiple signaling cascades. Pharmacological studies implicate this receptor in synaptic function/plasticity and cognitive behaviors. We employ sophisticated genetic tools (conditional gene deletion, in utero electroporation) to understand the contribution of mGluR5 signaling in specific neuronal populations to sensory circuit formation, synaptic function/plasticity, and behavior. We have found distinct roles for mGluR5 in cortical excitatory neurons to instruct dendritic morphogenesis, in regulating the excitatory-inhibitory balance of cortical circuits, and in behaviors. The implications of these studies are numerous, since excitation-inhibition imbalance is an important contributor to many neurological and psychiatric disorders. Furthermore, mGluR5 mutations have been identified in some ADHD and schizophrenic patients.
Elucidating the roles of NMNAT2 in maintaining neuronal health and in neuroprotection against neurodegeneration
Proper brain function requires an active maintenance program to sustain neuronal health. Environmental stressors detrimentally impact the nervous system, predisposing it to neuronal dysfunction and degeneration if neuroprotective mechanisms are weakened. Recent studies by others and us revealed that NMNATs (nicotinamide mononucleotide adenylyl transferases) maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 is the major NMNAT isoform expressed in the mammalian brain and is extremely labile, with a half-life of less than two hours. We have found that NMNAT2 abundance is significantly reduced in Alzheimer’s Disease brains. Using the FTDP-17 tauopathy animal model, rTg4510 mice, we found that NMNAT2 levels were substantially decreased prior to the onset of neurodegeneration. Most importantly, exogenous (viral) Nmnat2 expression in rTg4510 hippocampus reduced neurodegeneration and the accumulation of toxic tau species. Furthermore, reducing NMNAT2 function in mice leads to axonal deterioration. These findings indicate that NMNAT2 is a potential target for therapeutic interventions in neurodegeneration. To identify approaches to enhance NMNAT2 abundance as a way to provide neuroprotection or to prevent NMNAT2 down-regulation following a pathological insult, we have validated and optimized a primary neuron-based, high-throughput-screening (HTS) assay to identify NMNAT2 activators. In addition, we have established both in vitro and in vivo models to determine the efficacy of the neuronal protection phenotypes associated with NMNAT2 overexpression. These screens will allow us to identify novel strategies for enhancing NMNAT2 stability/abundance.
- Hsiao-Tuan Chao, Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Shiaoching Gong, Hui-Chen Lu, Nathaniel Heintz, Marc Ekker, John L.R. Rubnenstein, Jeffrey L, Noebels, Christian Rosenmund, Huda Y. Zoghbi (2010) “GABAergic dysfunction mediates autism-like stereotypies and numerous features of Rett syndrome”, Nature, 468(7321):263-9.
- Carlos J Ballester Rosado, Michael J Albright, Chia-Shan Wu, Chun-Chieh Liao, Jie Zhu, Shen-Ju Chou, Dennis D O'Leary, Li-Jen Lee, and Hui-Chen Lu (2010) “mGluR5 in cortical excitatory neurons exerts both cell autonomous and nonautonomous influences on cortical somatosensory circuit formation”, Journal of Neuroscience, 30:16896-909.
- Chia-Shan Wu, Carlos J Ballester Rosado, Hui-Chen Lu (2011) “What can we learn from “BARRELs” -the rodent barrel cortex as a model to study the establishment of neural circuits”, European J. Neuroscience, 34:1663-76.
- Cecilia Ljungberg, Yousuf Ali, Jie Zhu, Chia-Shan Wu, Kazuhiro Oka, R.Grace Zhai, Hui-Chen Lu (2012) “CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy”, Human Mol. Genetics, 15:251-67.
- Yousuf O. Ali, David Li-Kroeger, Hugo Bellen, R. Grace Zhai, Hui-Chen Lu (2013) NMNATs, evolutionary conserved neuronal maintenance factors, Trends in Neuroscience, 36:632-40.
- Chris P. Jew, Chia-Shan Wu, Hao Sun, Jie Zhu, Jui-Yen Huang, Dinghui Yu, Nicholas J. Justice, Hui-Chen Lu (2013) “mGluR5 ablation in cortical glutamatergic neurons increases novelty-induced locomotion”, Plos One, 8:e70415.
- Kihoon Han,J. Lloyd Holder Jr, Christian P. Schaaf, Hui Lu, Hongmei Chen, Hyojin Kang, Jianrong Tang, Zhenyu Wu, Shuang Hao, Sau Wai Cheung, Peng Yu, Hao Sun, Amy M. Breman, Ankita Patel, Hui-Chen Lu, Huda Y. Zoghbi (2013) “SHANK3 duplication causes a hyperkinetic neuropsychiatric disorder with unique pharmacogenetic properties”, Nature, 503:72–77.
- Chia-Shan Wu, Daniel Morgan, Chris P. Jew, Chris Haskins, Mary-Jeanette Andrews, Corinne M. Spencer, Traci Czyzyk, Heather Bradshaw, Ken Mackie, Hui-Chen Lu (2013) “Long-term consequences of perinatal fatty acid amino hydrolase inhibition”, in press for British J. Pharmacology.
Honors and Awards
- Deborah K. Martin Achievement Award in Biomedical Research (1997)
- Markey Charitable Trust Foundation Graduate Student Fellowship (1996-1997)
- NIH NRSA postdoctoral fellowship F32NS11034
- NARSAD Young Investigator Award (2008-2010)
- AHA-Texas Affiliate Beginning Grant-in-Aid (Starter Award) (2004-2006)