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The Huang lab is interested in studying the molecular, cellular, and circuit mechanisms underlying autism spectrum disorders, neuropsychiatric disorders, and epilepsy. We currently focus on Smith-Magenis syndrome (SMS), a childhood brain disorder associated with intellectual disability, epilepsy, obesity, autism, and neuropsychiatric features. SMS is caused by 17p11.2 deletion or loss of the Retinoic Acid Induced 1 (RAI1) gene. The Huang lab uses genetic, molecular, cell biological, and modern neuroscience techniques to (1) determine the function of Rai1 and (2) develop disease-modifying therapies. Here are some highlights of our original discoveries:
Decipher the molecular neurobiology of autism-related neurodevelopmental disorders
Develop precision gene and pharmacological therapies for treating autism-related neurodevelopmental disorders
Decipher the molecular neurobiology of autism-related neurodevelopmental disorders
- We generated the first Rai1 conditional knockout mouse model (Rai1-flox mice) and uncovered the molecular function of Rai1 and specific neuronal substrates underlying neurobehavioral features in SMS (Huang WH et al., Neuron, 2016). Using iDISCO+ whole brain clearing and imaging techniques, we found that Rai1 ablation from the cortical excitatory neurons increases expression of the ion channel Cav3.1 and enhances excitability of the hippocampus dentate gyrus granule cells (Chang YT et al., PNAS, 2022). This is the first in vivo mechanism explaining how SMS brains become hyperexcitable
- Currently, we are investigating how Rai1 dosage is regulated and how Rai1 dosage imbalance in different neuronal subtypes drives molecular, neural circuit, and behavioral deficits
Develop precision gene and pharmacological therapies for treating autism-related neurodevelopmental disorders
- We provide the first in vivo evidence that SMS disease features in mice are reversible by postnatal genetic reactivation of Rai1 (Huang WH et al., PNAS, 2018). Building on this work, we performed AAV/CRISPR activation-mediated gene therapy to increase Rai1 levels in vivo and successfully rescues selective disease features in SMS mice (Chang HC et al., J Biol Chem., 2023). This is the first successful gene therapy by targeting the remaining Rai1 allele in SMS mice
- We developed a neurotrophic factor gene therapy that fully rescues social deficits, obesity, and metabolic features in SMS mice by genetically increasing Bdnf signaling (Javed S et al., Hum Mol Genet., 2022)
- Currently, we are searching for Rai1 upstream and downstream molecules that can serve as therapeutic targets for SMS