Graduate Institute of Clinical Medical Sciences

Research Core Overview

We aim to bridge basic neuroscience and translational medicine by mapping the root causes of neurodevelopmental disorders to develop targeted, disease-modifying therapies." Our research focuses on three major directions: "Microbiota-Gut-Brain Axis Neuroscience," "Synaptic Glutamate Receptor Gating and Trafficking," and "RNA-targeted and AI-driven Precision Therapeutics". We investigate how genetic variations and early environmental stress affect neuronal morphology, synaptic connectivity, and neural circuit functions, which in turn trigger excitotoxicity, neuroinflammation, and neuronal death. Concurrently, we integrate psychobiotics, nucleic acid drugs, and small-molecule therapeutic technologies to establish a cross-scale translational research framework that spans "microbiota regulation – synaptic pathology – precision therapy," thereby driving mechanism-guided treatments for neurodevelopmental disorders.

1. Psychobiotics and Gut-Brain Axis Regulation: Microbiota, Oxytocin, and Synaptic Repair

In collaboration with Bened Biomedical and the team of Distinguished Professor Ying-Chieh Tsai from National Yang Ming Chiao Tung University, our team deeply analyzes the neuromodulatory mechanisms of the psychobiotic Lactiplantibacillus plantarum PS128. The psychobiotic L. plantarum PS128 can improve social and spatial memory deficits in valproic acid (VPA)-induced autism spectrum disorder (ASD) mouse models. It restores dendritic branching and dendritic spine density in the hippocampus and prefrontal cortex. It also elevates oxytocin levels in the paraventricular nucleus of the hypothalamus, enhances hippocampal oxytocin receptor signaling, and increases the abundance of intestinal Bifidobacterium. Further research confirms that oxytocin receptor signaling is an essential link for L. plantarum PS128 to exert its behavioral improvement effects. Moving forward, we will continue to clarify the causal relationships among the vagus nerve, microbial metabolites, and oxytocin neural circuits to create probiotic intervention therapies that possess both clear mechanisms of action and clinical translation potential.

2. Glutamate Receptor Gating and Synaptic Pathology: From Genetic Variation to ASD/ID

In collaboration with Dr. Shu-Ling Chiu from Academia Sinica and Academician Richard L. Huganir's team at Johns Hopkins University, our team utilizes Gria1-A636T gene knock-in mice. We combine electrophysiology, magnetic resonance imaging (MRI), neuronal morphology analysis, calcium imaging, and animal behavioral analysis to systematically dissect the neurodevelopmental pathology triggered by AMPA receptor dysfunction. Studies have confirmed that the A636T mutation causes calcium-permeable AMPA receptors (CP-AMPARs) to abnormally persist during neurodevelopment. This leads to excessive calcium influx, synaptic hyperexcitotoxicity, loss of dendrites and dendritic spines, neuroinflammation, and neuronal death, resulting in progressive hippocampal atrophy. Ultimately, this leads to ASD/intellectual disability (ID)-like social and cognitive deficits. This research direction aims to understand the complete pathogenic context of "receptor gating -calcium homeostasis -synaptic structure -neural circuit -behavioral phenotype". Furthermore, it explores the regulatory mechanisms of AMPA receptor intracellular trafficking and synaptic plasticity to identify key therapeutic targets capable of protecting neurons and delaying or preventing neural circuit degeneration.

3. RNA-targeted and AI-driven Precision Therapeutics: ASO and AMPAR Small-Molecule Drugs

To address the excitotoxicity triggered by GRIA1-A636T and other ion channel mutations, our team is developing two complementary precision medicine strategies:

First: Developing allele-specific antisense oligonucleotides (ASOs) to selectively reduce the expression of mutant mRNA while preserving the normal function of wild-type GluA1. Current animal studies show that a single intracerebroventricular administration in neonatal mice can significantly reduce neuronal death and neuroinflammation, restore dendritic structures, and improve social, learning, and memory functions in adult mice, demonstrating the therapeutic potential of early precision intervention.

Second: In the future, we will establish an AI-driven small-molecule drug screening platform. This platform will integrate receptor structural analysis, virtual compound screening, GCaMP calcium imaging, and electrophysiological validation to discover candidate drugs that can selectively inhibit pathological CP-AMPARs. This will block excessive calcium influx while retaining normal neurotransmission functions. We will further utilize humanized mice and patient-derived induced pluripotent stem cell (iPSC) models to systematically evaluate the efficacy, safety, and optimal therapeutic windows of candidate therapies, accelerating the translation of research findings into clinical applications.

Laboratory Vision

Our laboratory stands on three pillars: "Gut-Brain Axis, Synaptic Pathology, and RNA Targeting & AI Drug Development." We drive mechanism-guided research from molecular to behavioral levels, integrating multi-layered strategies including psychobiotics, ASOs, and small-molecule drugs. We fully bridge basic neuroscience, disease models, and clinical precision medicine, striving to establish an integrated disease-modifying approach for neurodevelopmental disorders to transform scientific discoveries into innovative therapies.

Recent Publications

1. Chen CM, Wu CC, Kim Y, Hsu WY, Tsai YC, & Chiu SL (2024). Enhancing social behavior in an autism spectrum disorder mouse model: investigating the underlying mechanisms of Lactiplantibacillus plantarum intervention. Gut Microbes, 16(1), 2359501 (IF=15.3)

2. Chiu SL*, Chen CM*, and Huganir RL. 2023. ICA69 regulates activity-dependent synaptic strengthening and learning and memory. Frontiers in Molecular Neuroscience, 16, 1171432.  *Co-first authors. (IF=4.0)

3. Chen CM*, Cheng SH*, Chen YH, Wu CC, Hsu CC, Lin CT and Tsai YC. (2022)   Supplementation with heat-inactivated Lactobacillus paracasei K47 ameliorates allergic asthma in mice by regulating the Th1/Th2 balance. Beneficial Microbes, 13(1), 73-82.  *Co-first authors. (IF=3.5)

4. Chen CM*, Wu CC*, Huang CL, Chang MY, Cheng SH, Lin CT, and Tsai YC. (2022) Lactobacillus plantarum PS128 promotes intestinal motility, mucin production, and serotonin signaling in mice. Probiotics and Antimicrobial Proteins, 14(3), 535-545 *Co-first authors. (IF=5.3)

5. Chiu SL, Diering G, Ye B, Takamiya K, Chen CM, Jiang Y, Niranjan T, Schwartz CE, Wang T and Huganir RL. (2017) GRASP1 regulates synaptic plasticity and memory through endosomal recycling of AMPA receptors. Neuron 93(6): 1405-1419 (IF=16.9)

6. Chen CM, Orefice LL, Chiu SL, LeGates TA, Hattar S, Huganir RL, Zhao H, Xu B, Kuruvilla R. (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci 114(4): 619-28. (IF=9.5)

7. Subasini C, Dhanesh SB, Chen CM, Riya PA, Meera V, Divya TS, Kuruvilla R, Buttler K, James J. (2017) Wnt5a is a crucial regulator of neurogenesis during cerebellum development. Sci Rep 16; 7 42523:1-17 (IF=4.9)