NO. 56

CIMR Wednesday Lecture Series

Time:

Wednesday, Feb. 19 2025, 4:00 p.m.

Location:

Yifu Lecture Hall, North Basic Research Building 

Host：

Jiawei Liu (刘佳伟)

Ph.D. Candidate, Yuval Rinkevich Lab

Chinese Institutes for Medical Research, Beijing

Speaker：

Hailan Hu (胡海岚)

Professor

School of Medicine

Zhejiang University

TITLE：

Decoding Neural Mechanisms of Depression: A New Perspective Based on the Pharmacological Effects of Ketamine

ABSTRACT:

Depression, a highly polygenic and heterogeneous disorder, has long eluded mechanistic understanding due to the limitations of traditional forward genetic approaches. Here, we propose a complementary strategy: leveraging the rapid, targeted action of Ketamine—a potent NMDA receptor (NMDAR) antagonist with robust antidepressant effects—to reverse-engineer the primary neural mechanisms underlying depression. By dissecting how Ketamine acutely disrupts pathological circuitry, we aim to bypass indirect downstream effects and pinpoint core drivers of the disease.

Our recent work demonstrates that Ketamine silences NMDAR-dependent burst firing in the lateral habenula (LHb), the brain’s “anti-reward” hub. In depressive-like states, LHb hyperactivity suppresses downstream aminergic reward circuits, perpetuating anhedonia and emotional dysregulation. Ketamine’s rapid antidepressant action arises from its ability to suppress this hyperactivity, disinhibiting reward pathways within minutes. Furthermore, we identified that Ketamine’s sustained efficacy stems from a trapping blockade of LHb-NMDARs—a pharmacological mechanism that prolongs receptor inhibition even after drug clearance. Finally, Ketamine’s brain-region specificity is mediated by use-dependent NMDAR inhibition, selectively targeting hyperactive LHb neurons while sparing baseline activity in other regions. Collectively, by mapping Ketamine’s site-specific modulation of cellular and circuit dynamics, we uncover a unified framework linking NMDAR dysfunction to depression etiology and treatment.

Building on this, our recent work extends this framework beyond NMDARs, identifying two additional ion channels as critical mediators of LHb bursts and antidepressant efficacy. Through the characterization of one these channels, a glia-specific potassium channel Kir4.1, we identified a novel form of neuron-glia interaction, whereby astrocytic processes tightly envelop neuronal soma to regulate neuronal bursts. I will present our ongoing work delineating how neurons and astrocytes dynamically interact in the LHb to regulate stress response and depressive-like behaviors.

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