Prof. Zhitao Hu (胡志濤)

Biography

• 2024-Present, Associate Professor, Department of Neuroscience, City University of Hong Kong, Hong Kong SAR
• 2022-2023, Associate Professor, Queensland Brain Institute, the University of Queensland, Australia
• 2015-2022, Assistant Professor, Queensland Brain Institute, the University of Queensland, Australia
• 2008-2015, Postdoctoral Fellow, Department of Molecular Biology, Massachusetts General Hospital

Research Interests and Goals

The research goals of my laboratory are to characterize the biochemical mechanisms governing synaptic transmission. Synapses comprise over 1000’s of proteins, concentrated into a tiny cellular structure (< 1μm in diameter), the point of physical contact between the pre- and post-synaptic cell. Understanding how these tiny structures function is important and interesting for several reasons. First, cognition and behavior are encoded by signals transmitted between neurons at synapses. Second, in the last 10 years it has increasingly become apparent that many psychiatric disorders are likely caused by disrupted synaptic function. Third, human genetic studies have identified 1000’s of gene mutations in that cause psychiatric disorders (e.g. Autism, Alzheimer’s, ADHD et al.). Thus, an important goal is to understand how these mutations alter synaptic transmission. Over the past 50 years, electrophysiological studies have provided a vast wealth of information concerning the functional properties of synapses. What has been lacking is a genetically accessible model to determine how this complex web of proteins dictates circuit activity and behavior. C. elegans has been emerging as a good model organism to address these questions, particularly the basic and fundamental questions in neuroscience.

Over the last few decades, one of the most important objectives in the field of neuroscience has been to understand the molecular and cellular mechanisms that regulate neurotransmitter release, which drives neuronal communication in the nervous system. Many model organisms have been used to address this question, including the mouse, fly, zebrafish, nematodes and octopus. Among these organisms, C. elegans has emerged as a powerful genetic model to study synaptic function. In the past 20 years, numerous studies in C. elegans have significantly promoted the development of this field, with the development of sophisticated electrophysiology and imaging techniques in this organism. Combining the electrophysiological recording, cellular imaging, molecular biology, and biochemistry approaches, we are currently focusing on four lines of research:

1. Molecular mechanisms for E/I balance. In human brains, maintaining the balance between excitation and inhibition (E/I balance) is key for the normal function of the nervous system. Imbalances in excitation/inhibition have been linked to several neurological disorders such as epilepsy, schizophrenia, and autism. Thus, understanding the molecular underpinnings of E/I imbalance will provide significant insights into the pathogenesis of these disorders. We have identified synaptic mutants that display differential defects at cholinergic and GABAergic synapses, indicating that excitatory and inhibitory neurotransmitter release are differentially regulated.

2. Kinetics regulation in synaptic vesicle release. Neurotransmitter release is tightly regulated and thought to occur in a number of steps, in which the vesicles are tethered to the release site, primed and fused with the plasma membrane. The final fusion is quite fast (occurs in milliseconds) in response to calcium influx. During this process, the vesicles can be released at different kinetics, termed fast and slow release. Over the past few decades, a large number of synaptic proteins affecting the amount of synaptic release have been identified. However, the effects of the experimental manipulation on the release kinetics have not been largely investigated. Understanding how release kinetics is determined has broad implications. The speed of the neurotransmission limits the efficiency and the communication rate between neurons and strongly influences local circuit dynamics. The release kinetics has profound effects on circuit development and cognition, as well. We are focusing on synaptic proteins that affect release kinetics to determine the underlying molecular mechanism.

3. Molecular/Cellular mechanisms for different release forms. Neurotransmitters can be released in two forms: evoked fusion after an action potential, and spontaneous fusion(termed “minis” or mEPSC). Increasing evidence shows that the spontaneous and evoke do not always change at the same trend, indicating that different fusion machinery for these two release forms. Although the physiological function is still uncertain, spontaneous release has been proposed to be important in multiple processes: including long-term facilitation induction, homeostatic synaptic plasticity modulation, postsynaptic receptors clustering at the release site, etc. There is evidence that vesicles driving these two modes of release are supplied by different pools. For example, studies have demonstrated that a large portion of spontaneously released vesicles are drawn from a pool other than the readily releasable pool that normally gives rise to evoked release. Despite these efforts on spontaneous and evoked release, the molecular mechanism, however, remains unclear. We will focus on those mutants in which the two kinds of release are differently regulated and determine the cellular mechanism.

4. Synaptic mechanisms of neurological disorders/diseases. Recent advances in genomic and bioinformatics technologies have identified DNA variants that are associated with neurological disorders like Autism and motor neuron disease. Demonstrating a functional role for the genes linked to the disorders is the first step in prioritizing follow-up studies. As a widely used tool in neuroscience, C. elegans provides a cost-effective strategy to validate the genes identified in human genetic studies by studying their functional role in synaptic transmission. We will focus on those candidate genes and dissect their functional importance in synapses.

Selected Publications

Articles (under review and in revision manuscripts are included)

• Zeng W. X., Liu H., Tian F. M., Qian K. Y., Hao Y., Yu B., Zeng X. T., Kong Y., Liu R., Li Q., Gao S. B. , Hu Z.*, and Tong X. J.*. CaMKII mediates sexually dimorphic synaptic transmission at neuromuscular junctions in C. elegans. Journal of Cell Biology, Accepted, (2023). (*, corresponding authors)
• Sohee J., Li L., Hu Z., and Richmond J. Tomosyn regulates the cooperation of SNT-1 and SNT-3. under review, (2023).
• Hao Y., Liu H., Li L., Zeng X. T., Zeng W. X., Qian K. Y., Chi M. X., Hu Z., and Tong X. J. CaMKII-triggered anterograde signals recruit GABAARs to mediate inhibitory synaptic transmission and plasticity at NMJs. Nature Communications, 14: 1436 (2023).
• Zhang L., Li L., Liu H., Wei Z. Q., Hu Z.*, and Ma C.*. Recruitment of Munc13 to PI(4,5)P2 fusion sites guided by the C2PH module of CAPS is essential for Ca2+-regulated vesicle exocytosis. Structure, doi.org/10.1016/j.str.2023.02.004 (2023). (*, corresponding authors)
• Li L., Liu H., Qian K. Y., Stephen N., Zeng X. T., Kaplan J. M., Tong X. J., and Hu Z. CASK and FARP localize two classes of post-synaptic ACh receptors thereby promoting cholinergic transmission. PLoS Genetics, 18(10): e1010211 (2022).
• Qian K. Y., Zeng W. X., Hao Y., Zeng X. T., Liu H., Li L., Chen L., Tian F. M., Chang C., Hall Q., Song C. X., Gao S., Hu Z., Kaplan J. M., Li Q., and Tong X. J. Male pheromones modulate synaptic transmission at the C. elegans neuromuscular junction in a sexually dimorphic manner. eLife 10, (2021).
• Padmanarayana M., Liu H., Michelassi F., Li L., Betensky D., Dominguez M. J., Sutton R. B., Hu Z., and Dittman J. S. A unique C2 domain at the C terminus of Munc13 promotes synaptic vesicle priming. Proceedings of the National Academy of Sciences of the United States of America 118, (2021).
• Liu H., Li L., Sheoran S., Yu Y., Richmond J. E., Xia J., Tang J., Liu J., and Hu Z. The M domain in UNC-13 regulates the probability of neurotransmitter release. Cell Reports 34, 108828, (2021).
• Liu H., Li L., Krout M., Sheoran S., Zhao Q., Chen J., Liu H., Richmond J. E., and Hu Z. Protocols for electrophysiological recordings and electron microscopy at C. elegans neuromuscular junction. STAR Protoc 2, 100749, (2021).
• Li L., Liu H., Krout M., Richmond J. E., Wang Y., Bai J., Weeratunga S., Collins B. M., Ventimiglia D., Yu Y., Xia J., Tang J., Liu J., and Hu Z. A novel dual Ca2+ sensor system regulates Ca2+-dependent neurotransmitter release. The Journal of Cell Biology 220, (2021).
• Snieckute G., Baltaci O., Liu H., Li L., Hu Z., and Pocock R. mir-234 controls neuropeptide release at the Caenorhabditis elegans neuromuscular junction. Molecular and cellular neurosciences 98, 70-81, (2019).
• Liu H., Li L., Nedelcu D., Hall Q., Zhou L., Wang W., Yu Y., Kaplan J. M., and Hu Z. Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans. eLife 8, (2019).
• Li L., Liu H., Hall Q., Wang W., Yu Y., Kaplan J. M., and Hu Z. A hyperactive form of unc-13 enhances Ca2+ sensitivity and synaptic vesicle release probability in C. elegans. Cell Reports 28, 2979-2995 e2974, (2019).
• Tikiyani V., Li L., Sharma P., Liu H., Hu Z., and Babu K. Wnt secretion is regulated by the tetraspan protein HIC-1 through its interaction with neurabin/NAB-1. Cell Reports 25, 1856-1871 e1856, (2018).
• Sharma P., Li L., Liu H., Tikiyani V., Hu Z.*, and Babu K.*. The Claudin-like protein HPO-30 is required to maintain LAChRs at the C. elegans neuromuscular junction. The Journal of Neuroscience 38, 7072-7087, (2018). (*, corresponding authors)
• Liu H., Li L., Wang W., Gong J., Yang X., and Hu Z. Spontaneous vesicle fusion is differentially regulated at cholinergic and GABAergic synapses. Cell Reports 22, 2334-2345, (2018).
• Li L., Liu H., Wang W., Chandra M., Collins B. M., and Hu Z. SNT-1 functions as the Ca2+ sensor for tonic and evoked neurotransmitter release in Caenorhabditis elegans. The Journal of Neuroscience 38, 5313-5324, (2018).
• Tong X. J., Lopez-Soto E. J., Li L., Liu H., Nedelcu D., Lipscombe D., Hu Z., and Kaplan J. M. Retrograde synaptic inhibition is mediated by alpha-neurexin binding to the alpha2delta subunits of N-type calcium channels. Neuron 95, 326-340 e325, (2017).
• Michelassi F., Liu H., Hu Z., and Dittman J. S. A C1-C2 module in Munc13 inhibits calcium-dependent neurotransmitter release. Neuron 95, 577-590 e575, (2017).
• Du H., Zhang M., Yao K., and Hu Z. Protective effect of Aster tataricus extract on retinal damage on the virtue of its antioxidant and anti-inflammatory effect in diabetic rat. Biomed Pharmacother 89, 617-622, (2017).
• Tong X. J.*, Hu Z.*, Liu Y., Anderson D., and Kaplan J. M. A network of autism linked genes stabilizes two pools of synaptic GABAA receptors. eLife 4, e09648, (2015). (*, first authors)
• Hu Z., Vashlishan-Murray A. B., and Kaplan J. M. NLP-12 engages different UNC-13 proteins to potentiate tonic and evoked release. The Journal of Neuroscience 35, 1038-1042, (2015).
• Choi S., Taylor K. P., Chatzigeorgiou M., Hu Z., Schafer W. R., and Kaplan J. M. Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release. PLoS Genetics 11, e1005359, (2015).
• Sun Y., Hu Z., Goeb Y., and Dreier L. The F-box protein MEC-15 (FBXW9) promotes synaptic transmission in GABAergic motor neurons in C. elegans. PloS One 8, e59132, (2013).
• Hu Z., Tong X. J., and Kaplan J. M. UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans. eLife 2, e00967, (2013).
• Thompson-Peer K. L., Bai J., Hu Z., and Kaplan J. M. HBL-1 patterns synaptic remodeling in C. elegans. Neuron 73, 453-465, (2012).
• Hu Z., Hom S., Kudze T., Tong X. J., Choi S., Aramuni G., Zhang W., and Kaplan J. M. Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans. Science 337, 980-984, (2012).
• Hao Y., Hu Z., Sieburth D., and Kaplan J. M. RIC-7 promotes neuropeptide secretion. PLoS Genetics 8, e1002464, (2012).
• Chan J. P., Hu Z., and Sieburth D. Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release. Genes & Development 26, 1070-1085, (2012).
• Martin J. A.*, Hu Z.*, Fenz K. M., Fernandez J., and Dittman J. S. Complexin has opposite effects on two modes of synaptic vesicle fusion. Current Biology 21, 97-105, (2011). (*, first authors)
• Hu Z., Pym E. C., Babu K., Vashlishan Murray A. B., and Kaplan J. M. A neuropeptide-mediated stretch response links muscle contraction to changes in neurotransmitter release. Neuron 71, 92-102, (2011).
• Babu K., Hu Z., Chien S. C., Garriga G., and Kaplan J. M. The immunoglobulin super family protein RIG-3 prevents synaptic potentiation and regulates Wnt signaling. Neuron 71, 103-116, (2011).
• Bai J., Hu Z., Dittman J. S., Pym E. C., and Kaplan J. M. Endophilin functions as a membrane-bending molecule and is delivered to endocytic zones by exocytosis. Cell 143, 430-441, (2010).
• Hu Z., Chen M. R., Ping Z., Dong Y. M., Zhang R. Y., Xu T., and Wu Z. X. Synaptotagmin IV regulates dense core vesicle (DCV) release in LbetaT2 cells. Biochemical and Biophysical Research Communications 371, 781-786, (2008).
• Hu Z., Dun X., Zhang M., Zhu H., Xie L., Wu Z., Chen Z., and Xu T. PA1b, a plant peptide, induces intracellular [Ca2+] increase via Ca2+ influx through the L-type Ca2+ channel and triggers secretion in pancreatic beta cells. Sci China C Life Sci 50, 285-291, (2007).
• Liu H. S.*, Hu Z.*, Zhou K. M., Jiu Y. M., Yang H., Wu Z. X., and Xu T. Heterogeneity of the Ca2+ sensitivity of secretion in a pituitary gonadotrope cell line and its modulation by protein kinase C and Ca2+. The Journal of Cellular Physiology 207, 668-674, (2006). (*, first authors)
• Hu Z., Zhao P., Liu J., Wu Z. X., and Xu T. Alpha-latrotoxin triggers extracellular Ca(2+)-dependent exocytosis and sensitizes fusion machinery in endocrine cells. Acta Biochim Biophys Sin (Shanghai) 38, 8-14, (2006).
• Ge Q., Dong Y. M., Hu Z., Wu Z. X., and Xu T. Characteristics of Ca2+-exocytosis coupling in isolated mouse pancreatic beta cells. Acta Pharmacol Sin 27, 933-938, (2006).
• Yang H., Liu H., Hu Z., Zhu H., and Xu T. PKC-induced sensitization of Ca2+-dependent exocytosis is mediated by reducing the Ca2+ cooperativity in pituitary gonadotropes. The Journal of General Physiology 125, 327-334, (2005).

11 January 2024