https://scholar.dgist.ac.kr/handle/20.500.11750/1212 2026-10-03T23:47:29Z 2026-10-03T23:47:29Z Roh, Heegwang Kim, Dongwook Kim, Byeongchan Jeon, Younghyeon Malhotra, Shreya Kim, Hyeonho Kim, Yeonghye Jacko, Martin Klein, Peter M. Lin, Chang Xu, Fei Soltesz, Ivan Um, Ji Won Ting, Alice Y. https://scholar.dgist.ac.kr/handle/20.500.11750/60854 2026-09-21T08:40:18Z 2026-07-31T15:00:00Z

Title: Light-activated tetanus neurotoxin for conditional proteolysis and inducible synaptic inhibition in vivo Author(s): Roh, Heegwang; Kim, Dongwook; Kim, Byeongchan; Jeon, Younghyeon; Malhotra, Shreya; Kim, Hyeonho; Kim, Yeonghye; Jacko, Martin; Klein, Peter M.; Lin, Chang; Xu, Fei; Soltesz, Ivan; Um, Ji Won; Ting, Alice Y. Abstract: The light chain of tetanus neurotoxin (TeNT) is a metalloprotease that potently inhibits synaptic transmission by cleaving the endogenous vesicle fusion protein VAMP2, but its constitutive activity prevents spatiotemporal precision. To address this, we engineered light-activated TeNT (LATeNT) by inserting the light-sensitive LOV domain into an allosteric site and optimizing dynamic range via directed evolution. LATeNT's activity is undetectable in the dark, but the protease turns on after 10-20 min of weak blue-light exposure to potently inhibit synapses in vivo. Here we show that LATeNT works across multiple brain regions and at long-range axonal projections, with its effects reversible in 24 h. LATeNT enabled us to discover a hippocampal interneuron population that regulates anxiety-like behaviors and demonstrate the importance of postsynaptic endocannabinoid exocytosis for depolarization-induced suppression of inhibition in vivo. Beyond neuroscience, LATeNT regulated endogenous insulin secretion from pancreatic beta cells and converted drug exposure, elevated Ca2+ or receptor activation into transgene expression or reporter secretion in HEK293T cells. With a large dynamic range, high light sensitivity and sustained effect, LATeNT enables versatile, spatiotemporally resolved proteolysis across diverse biological systems.

2026-07-31T15:00:00Z Lee, Yelin Ko, Jaewon Um, Ji Won https://scholar.dgist.ac.kr/handle/20.500.11750/60850 2026-09-21T04:40:16Z 2026-07-31T15:00:00Z

Title: Cytokine-mediated immune-to-brain signaling in neural circuit disorders Author(s): Lee, Yelin; Ko, Jaewon; Um, Ji Won Abstract: Neuroinflammation has emerged as a fundamental driver of neural circuit dysfunctions across a spectrum of neurodevelopmental and psychiatric disorders. Beyond classical neuroimmune pathologies, accumulating evidence indicates that systemic inflammatory states - including those elicited by infection, metabolic dysfunction, stress, or peripheral immune activation - induce profound and long-lasting alterations in brain development and function. Cytokines act as critical molecular mediators of this peripheral-to-central immune communication, precisely orchestrating microglial activation in a spatiotemporally restricted manner. Inflammasome-dependent signaling, particularly NLRP3 activation and subsequent cytokine release, has a central role in shaping microglial states during neuroinflammation. Here, we integrate current evidence linking systemic inflammation to microglial cytokine signaling programs and discuss how these cascades shape synaptic development, refinement, and circuit function. Although synapse pruning and cytokine-mediated microglial signaling jointly contribute to circuit remodeling, we highlight cytokine-driven microglial state amplification as a central mechanism linking systemic inflammation to neural circuit instability. We also highlight that specific cytokines can exert direct effects on neuronal populations - independent of microglial intermediates - to context-dependently modulate synaptic efficacy and circuit excitability. Finally, we evaluate the mechanisms linking systemic inflammation to brain dysfunction and highlight emerging translational opportunities, including the therapeutic repurposing of cytokine-targeting and immunomodulatory agents for neuropsychiatric interventions.

2026-07-31T15:00:00Z Lee, Changjun Lee, Yelin Jeong, Woo Chan Hwang, Inhwa Bae, Harin Shim, Do-Wan Jung, Hyeji Um, Ji Won Yu, Je-Wook https://scholar.dgist.ac.kr/handle/20.500.11750/60598 2026-08-10T07:10:16Z 2026-04-30T15:00:00Z

Title: Loss of astrocytic Bmal1 promotes blood-brain barrier disruption and synaptic dysfunction during systemic inflammation Author(s): Lee, Changjun; Lee, Yelin; Jeong, Woo Chan; Hwang, Inhwa; Bae, Harin; Shim, Do-Wan; Jung, Hyeji; Um, Ji Won; Yu, Je-Wook Abstract: Circadian rhythm disruption has been associated with the exaggerated inflammatory responses in peripheral tissues; however, its impact on neuroinflammation and blood-brain barrier (BBB) integrity remains unclear. Here, we identify the astrocytic circadian clock as a key regulator of BBB homeostasis during systemic inflammation. In a mouse model, circadian rhythm disruption for three weeks markedly increased BBB permeability in male mice, as evidenced by Evans blue leakage and myeloid cell infiltration into the brain parenchyma following lipopolysaccharide (LPS) challenge. Transcriptomic analyses using public datasets revealed that astrocytes exhibit the highest expression of core circadian clock genes among brain cell types. Accordingly, we generated tamoxifen-inducible, astrocyte-specific Bmal1-knockout (KO) mice. Deletion of Bmal1 in astrocytes significantly enhanced BBB leakage, astrogliosis and pericyte loss after LPS administration. Mechanistically, Bmal1-deficient astrocytes produced elevated levels of the chemokine CXCL5, which promoted CXCR2-dependent neutrophil recruitment into the brain. Pharmacological blockade of CXCR2 with SB225002 restored pericyte coverage and attenuated BBB disruption in astrocytic Bmal1 KO mice. Functionally, these mice exhibited impaired excitatory synaptic transmission following systemic inflammation, suggesting that astrocytic Bmal1 loss compromises neurovascular and synaptic integrity. Taken together, our findings demonstrate that astrocytic Bmal1 maintains BBB integrity and synaptic stability under inflammatory stress. This work also highlights astrocyte-intrinsic circadian regulation as a critical mechanism linking chemokine production to neurovascular vulnerability.

2026-04-30T15:00:00Z Lee, Dongsu Han, Kyung Ah Jeong, Hyeonyeong Ha, Go Eun Lee, Hyeongjin Kim, Beom Soo Park, Chanmi Piao, Yao Lee, Haeun Kim, Joon Yoon, Taek Han Kim, Seungjoon Kim, Byeongchan Shin, Jungsu Cho, Yujin Kang, Sunghyun Park, Han-Eol Um, Ji Won Sohn, Chang Ho Huguenard, John R. Ko, Jaewon Cheong, Eunji https://scholar.dgist.ac.kr/handle/20.500.11750/60358 2026-09-21T06:10:16Z 2026-03-31T15:00:00Z

Title: Juvenile-to-adult refinement of thalamic reticular circuits via LRRTM3 enables high-resolution sensory encoding Author(s): Lee, Dongsu; Han, Kyung Ah; Jeong, Hyeonyeong; Ha, Go Eun; Lee, Hyeongjin; Kim, Beom Soo; Park, Chanmi; Piao, Yao; Lee, Haeun; Kim, Joon; Yoon, Taek Han; Kim, Seungjoon; Kim, Byeongchan; Shin, Jungsu; Cho, Yujin; Kang, Sunghyun; Park, Han-Eol; Um, Ji Won; Sohn, Chang Ho; Huguenard, John R.; Ko, Jaewon; Cheong, Eunji Abstract: Sensory processing enables adaptive behavior by accurately encoding dynamic environmental stimuli. Within thalamocortical (TC) circuits, the thalamic reticular nucleus (TRN) functions as a key inhibitory gate that regulates cortical access to sensory input. While classical models posit that sensory circuits stabilize after early critical periods, we uncover a previously unrecognized phase of synaptic refinement in TRN circuitry extending from the juvenile period into adulthood. This late-stage remodeling is driven by a progressive reduction in corticothalamic (CT) excitatory input and is essential for enhancing sensory gain, response linearity, and stimulus discriminability. We identify LRRTM3, a TRN-enriched synaptic adhesion molecule, as a molecular gatekeeper of this process. TRN-specific deletion of LRRTM3 disrupts CT–TRN refinement, elevates TRN-mediated inhibition, and impairs fine tactile discrimination. These findings revise canonical views of sensory circuit maturation, revealing that LRRTM3-mediated juvenile-to-adult TRN plasticity is essential for the emergence of high-resolution sensory encoding in the adult brain.

2026-03-31T15:00:00Z