- Title Professor of Biology
- Education PhD, University of Toronto, 2001
- Web Address http://people.bu.edu/hman
- Email email@example.com
- Phone 617-358-4283
- Area of Interest Brain development, neuron morphogenesis, synapse formation, synaptic plasticity, AMPA type glutamate receptor, protein ubiquitination and degradation, autism, Intellectual disability, Alzheimer’s disease
Our research interests are focused on brain development, especially neuronal migration, morphogenesis, synapse formation, glutamate receptors and synaptic plasticity. We aim to understand the cellular and molecular processes implicated in neurodegenerative diseases and developmental disorders including autism, Angelman syndrome, intellectual disability and Alzheimer’s disease. We use diverse techniques including biochemistry, immunofluorescent staining, live imaging, virus injection, in utero electroporation, electrophysiology and animal behavior tests. We are currently working on the following directions.
AMPA Receptor (AMPAR) Trafficking and Turnover: Glutamatergic AMPARs are the primary mediators for neuronal communication underlying basal and higher brain functions. Cognitive and psychological functions and behavior are fundamentally affected by changes in glutamate receptors. We have found that AMPARs are subject to ubiquitination and proteasome-mediated degradation. We study the participating E3 ligases and DUB enzymes and the function of ubiquitination in AMPAR trafficking and turnover, as well as roles of AMPAR stability in brain function and in diseases such as Alzheimer’s disease.
Homeostatic Synaptic Plasticity (HSP): Neurons are able to restore their activity to a set-point level by altering AMPAR synaptic accumulation and thus synaptic strength. This type of synaptic plasticity is important for the maintenance of neuronal or network stability during development and maturation. Following a prolonged period of activity deprivation at a single synapse, individual synapses will adjust their strength homeostatically in a compensatory manner. We have demonstrated that microRNA 124 (miR124)-mediated generation of GluA2-lacking, calcium-permeable AMPARs plays a key role in the initiation of inactivity-dependent HSP, and an abnormality in this process leads to pathological over-scaling of HSP in Alzheimer’s disease.
Neurobiology of Autism Spectrum Disorders (ASD): We have identified the X-linked KIAA2022/KIDLIA gene as a new autism gene. Male patients with KIAA2022/KIDLIA deletions, or functional mutations, show autistic characteristics including repetitive behaviors, lack of communication and intellectual disability. With an increasing number of cases reported since the identification of KIAA2022, the gene has become one of the common candidate genes included in autism diagnostic screening. However, the neurobiological functions of KIAA2022 as an autism gene remain largely unknown. We have successfully created a KIAA2022 knockout mouse model which shows typical autism phenotypes as well as impairments in learning and memory. We find that loss of KIAA2022 results in suppression of dendritic growth, a decrease in spine number, synapse formation and synaptic transmission. We are investigating the underlying molecular mechanisms and also exploring means to rescue the molecular dysregulation and behavioral deficits in KIAA2022/KIDLIA knockout mice with the aim to provide therapeutic tools for clinical management of the disorder.
Neuronal Development and Growth: During neuronal development, neurons undergo dramatic morphological changes. A neuron developing from a simple round soma first extends multiple minor neurites, in which one neurite will polarize into an axon. The remaining neurites become dendrites, undergoing extensive growth and branching to form elaborate dendritic arbors. We are interested in how this highly complex neuronal morphology is determined, regulated and maintained, and, in the case of neurological diseases, impaired.
- Khatri N, Gilbert JP, Huo Y, Sharaflari R, Nee M, Qiao H, Man HY (2018) The maternal imprinted autism protein Ube3A/E6AP remodels dendritic arborization via XIAP ubiquitination and caspase 3-mediated pruning. J Neurosci 38(2): 363-378.
- Wang G, Li S, Gilbert J, Gritton HJ, Wang Z, Li Z, Han X, Selkoe DJ, Man HY (2017) Crucial roles for SIRT2 and AMPA receptor acetylation in synaptic plasticity and memory. Cell Reports 20(6): 1335-1347.
- Gilbert J, Shu S, Yang X, Lu Y M, Zhu L Q and Man HY (2016) β-amyloid triggers aberrant over-scaling of homoeostatic synaptic plasticity. Acta Neuropathol Commun. 4(1): 1.
- Gilbert J and Man H Y (2016) The X-linked autism protein KIAA2022/KIDLIA regulates neurite outgrowth via N-cadherin and δ-catenin signaling. eNeuro, Oct 2016 DOI: 10.1523/ENEURO.0238-16.2016.
- Hou Q, Ruan H, Gilbert J, Wang G, Ma Q, Yao WD, Man HY (2015) MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity. Nature Communication DOI: 10.1038.
- Van Maldergem L, Hou Q, Kalscheuer VM, Rio M, Doco-Fenzy M, Medeira A, de Brouwer AP, Cabrol C, Haas SA, Cacciagli P, Moutton S, Landais E, Motte J, Colleaux L, Bonnet C, Villard L, Dupont J, Man HY (2013) Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth. Human Molecular Genetics, 22(16): 3306-3314.
- Qingming H, Gilbert J, Man HY (2011) Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation. Neuron, 72 (5): 806-818.
- S Amato S, Liu X, Zheng B, Cantley L, Rakic P, Man HY (2011) AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization. Science, 332(6026): 247-51.
- BI 455/655 Developmental Neurobiology
- BI 599 Neurobiology of Synapses