Prof. HU Zhitao (胡志濤)

• 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

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.