As a physician-scientist in training with a PhD in neuroscience and ongoing medical studies, I aim to bridge basic science and clinical insight to address unmet needs in diseases of the brain. My doctoral work uncovered a therapeutic strategy targeting alternative splicing to restore synaptic function and behavioral deficits in a human neuropsychiatric-associated mouse model. Recently accepted for publication in Molecular Psychiatry, this work presents a step towards more precise and effective treatments for conditions such as schizophrenia, autism, Tourette’s syndrome, and intellectual disability.

The Hong Kong Laureate Forum is a unique opportunity to exchange ideas with global scientific leaders and young scholars across various disciplines. I am particularly drawn to the Forum’s mission of fostering interdisciplinary collaboration and promoting science among younger generations.

At the forum, I seek to contribute a perspective shaped by my diverse background in genetics, neurobiology, and clinical medicine, while learning from others recent advances in medicine, basic science, and the role of artificial intelligence in clinical settings. I hope that attending the forum will expand my intellectual horizons, enable meaningful collaborations, and inspire future projects that combines basic science with clinical application to improve human health.

Neuropsychiatric disorders such as schizophrenia, autism spectrum disorder, Tourette’s syndrome, and intellectual disability are often associated with mutations in NRXN1, which encodes the synaptic adhesion molecule neurexin-1. While most NRXN1-linked patient mutations are heterozygous deletions, the functional impact of Nrxn1 haploinsufficiency remains unclear.

Here, we characterize synaptic consequences of heterozygous Nrxn1 deletion in mice. Despite preserved synapse number, we observe a ~2-fold reduction in excitatory synaptic transmission in CA1 pyramidal neurons. This deficit is accompanied by impaired presynaptic neurotransmitter release and reduced postsynaptic AMPA/NMDA receptor responses. Remarkably, exclusion of exons at splice site 5 (S5) in the remaining wild-type Nrxn1 allele rescues synaptic transmission and restores neurexin-1 protein levels to near wild-type.

These findings identify S5 splicing as a key modulator of neurexin-1 protein levels and provide a proof-of-concept for therapeutic splicing interventions in NRXN1-associated neuropsychiatric disorders. Our study highlights an approach to functionally restore synaptic integrity in the context of a monogenic risk factor, with potential translational relevance to human disease.