Review
Neurosciences
John H. Krystal, Ege T. Kavalali, Lisa M. Monteggia
Summary: Ketamine is a channel blocker that targets NMDA receptors and has shown rapid antidepressant effects, providing a potential new treatment option for mood disorders. This discovery has not only given us a better understanding of the neurobiology of mood disorders, but also shed light on synaptic plasticity mechanisms for its treatment. In this review, we discuss the clinical aspects, synaptic and circuit mechanisms of ketamine, and how these insights can inform future studies for more effective treatments of neuropsychiatric disorders.
NEUROPSYCHOPHARMACOLOGY
(2023)
Article
Neurosciences
Tonghui Su, Yi Lu, Chaoying Fu, Yang Geng, Yelin Chen
Summary: This study demonstrates that the loss of GluN2A in adult mouse brains can elicit strong antidepressant-like responses without causing psychomimetic effects similar to Ketamine. The antidepressant effects of Ketamine and MK-801 are mainly mediated by the suppression of GluN2A rather than GluN2B.
NATURE NEUROSCIENCE
(2023)
Article
Neurosciences
Tonghui Su, Yi Lu, Chaoying Fu, Yang Geng, Yelin Chen
Summary: The study found that the loss of GluN2A in adult mice elicits antidepressant-like responses without causing psychomimetic effects similar to ketamine. The antidepressant effects of ketamine and MK-801 are mediated by the suppression of GluN2A, not GluN2B. Additionally, these drugs increase the excitability of hippocampal neurons through GluN2A.
NATURE NEUROSCIENCE
(2023)
Article
Clinical Neurology
Youge Qu, Jiajing Shan, Siming Wang, Lijia Chang, Yaoyu Pu, Xingming Wang, Yunfei Tan, Masayuki Yamamoto, Kenji Hashimoto
Summary: The study found that (R)-ketamine can produce rapid and long-lasting antidepressant-like effects in Nrf2 KO mice through TrkB signaling, improving depression-like behaviors and decreased synaptic protein expression.
EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE
(2021)
Article
Pharmacology & Pharmacy
Hai-Xia Chang, Wei Dai, Jin-Hao Bao, Jin-Feng Li, Ji-Guo Zhang, Yun-Feng Li
Summary: This study found that microglia played a key role in the rapid action of antidepressants ketamine and YL-0919. The rapid antidepressant effect of these drugs was blocked by depleting microglia, indicating the importance of microglia in this process.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Neurosciences
Ryota Shinohara, George K. Aghajanian, Chadi G. Abdallah
Summary: The discovery of the rapid-acting antidepressant effects of ketamine has revolutionized our approach to treating severe depression, while also presenting new challenges. It is increasingly crucial to focus on the downstream molecular mechanisms of ketamine and its effects on the brain circuitry and networks.
BIOLOGICAL PSYCHIATRY
(2021)
Article
Neurosciences
Jenessa N. Johnston, Bashkim Kadriu, Josh Allen, Jessica R. Gilbert, Ioline D. Henter, Carlos A. Zarate
Summary: The discovery of ketamine as a rapid-acting antidepressant has led to significant research on its mechanisms of action and identification of other similar compounds. Serotonergic psychedelics (SPs) have shown potential in treating depression, but conducting controlled trials and long-term clinical observation pose challenges. This review compares the psychoactive effects and mechanisms of action of ketamine and SPs and highlights their similarities in downstream mechanisms, such as mTORC1 signaling and GABAA receptor activity. However, research on SPs is still in its early stages compared to ketamine.
Review
Pharmacology & Pharmacy
Songbai Xu, Xiaoxiao Yao, Bingjin Li, Ranji Cui, Cuilin Zhu, Yao Wang, Wei Yang
Summary: Ketamine has rapid and sustained antidepressant-like actions, but its dissociation and psychotomimetic propensities limit its use for psychiatric indications. This review explores the mechanisms by which ketamine exerts its antidepressant effects, including enhancing AMPAR-mediated transmission and activating neuroplasticity and synaptogenesis pathways.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Youyi Zhang, Fei Ye, Tongtong Zhang, Shiyun Lv, Liping Zhou, Daohai Du, He Lin, Fei Guo, Cheng Luo, Shujia Zhu
Summary: Ketamine, as a non-competitive channel blocker of NMDA receptors, can produce rapid and long-lasting antidepressant effects. The S-ketamine enantiomer is found to be the more active antidepressant, with its binding pocket in the NMDA receptor involving key amino acids for interaction.
Article
Cell Biology
Kanzo Suzuki, Ji-Woon Kim, Elena Nosyreva, Ege T. Kavalali, Lisa M. Monteggia
Summary: Acute inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus, while RA signaling pathway can also elicit similar synaptic scaling independently of eEF2K function. Activation of RAR alpha by retinoic acid leads to rapid antidepressant effects similar to ketamine.
Article
Pharmacology & Pharmacy
Yuko Fujita, Yaeko Hashimoto, Hiroyo Hashimoto, Lijia Chang, Kenji Hashimoto
Summary: The study demonstrated that (R)-ketamine can alleviate inflammation symptoms and depression in DSS-induced UC mouse model by reducing colon shortening and elevated levels of interleukin-6 caused by DSS treatment. The beneficial effects were found to be dependent on TrkB stimulation, suggesting (R)-ketamine as a potential novel therapeutic drug for inflammatory bowel diseases like UC.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yulia V. Vakhitova, Tatiana S. Kalinina, Liana F. Zainullina, Anastasiya Yu. Lusta, Anna V. Volkova, Nikita V. Kudryashov, Tatiana A. Gudasheva, Alexander A. Shimshirt, Ilya A. Kadnikov, Mikhail V. Voronin, Sergei B. Seredenin
Summary: The study showed that chronic treatment with GSB-106 has antidepressant-like effects in mice under chronic stress, likely through regulation of BDNF-TrkB signaling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Ji-Woon Kim, Kanzo Suzuki, Ege T. Kavalali, Lisa M. Monteggia
Summary: Acute administration of (R,S)-ketamine produces rapid and sustained antidepressant effects by blocking NMDA receptors and inducing a novel form of synaptic plasticity in the hippocampus. This triggers downstream signaling events and transcriptional changes that contribute to the antidepressant effects. This review explores the intracellular signaling pathway triggered by ketamine and its connection to synaptic plasticity and sustained antidepressant effects.
TRENDS IN MOLECULAR MEDICINE
(2023)
Article
Multidisciplinary Sciences
Shuangshuang Ma, Min Chen, Yihao Jiang, Xinkuan Xiang, Shiqi Wang, Zuohang Wu, Shuo Li, Yihui Cui, Junying Wang, Yanqing Zhu, Yan Yang, Huan Ma, Shumin Duan, Haohong Li, Yan Yang, Christopher J. Lingle, Hailan Hu
Summary: Ketamine, a potent antidepressant, continues to suppress neuronal firing and block NMDARs in the brain for up to 24 hours after a single injection. This sustained effect is not due to endocytosis, but rather the trapping of ketamine in NMDARs. By modulating the activity of NMDARs, the duration of ketamine action can be controlled, providing new opportunities for therapeutic use of ketamine.
Article
Multidisciplinary Sciences
Linda D. Simmler, Yue Li, Lotfi C. Hadjas, Agnes Hiver, Ruud van Zessen, Christian Luscher
Summary: Ketamine does not induce synaptic plasticity in the nucleus accumbens despite eliciting dopamine transients, due to the rapid off-kinetics of the dopamine transients and NMDAR antagonism. However, it supports reinforcement through NMDAR antagonism in GABA neurons of the ventral tegmental area, which is quickly terminated by type-2 dopamine receptors on dopamine neurons.
Article
Neurosciences
Megumi Adachi, Pei-Yi Lin, Heena Pranav, Lisa M. Monteggia
BIOLOGICAL PSYCHIATRY
(2016)
Article
Multidisciplinary Sciences
Zhenzhong Ma, Tong Zang, Shari G. Birnbaum, Zilai Wang, Jane E. Johnson, Chun-Li Zhang, Luis F. Parada
NATURE COMMUNICATIONS
(2017)
Article
Biology
Bishakha Mona, Ana Uruena, Rahul K. Kollipara, Zhenzhong Ma, Mark D. Borromeo, Joshua C. Chang, Jane E. Johnson
Article
Biology
Erinn S. Gideons, Pei-Yin Lin, Melissa Mahgoub, Ege T. Kavalali, Lisa M. Monteggia
Article
Neurosciences
Lisa M. Monteggia, Pei-Yi Lin, Megumi Adachi, Ege T. Kavalali
Article
Cell Biology
Pei-Yi Lin, Ege T. Kavalali, Lisa M. Monteggia
Article
Neurosciences
Pei-Yi Lin, Natal L. Chanaday, Patricia M. Horvath, Denise M. O. Ramirez, Lisa M. Monteggia, Ege T. Kavalali
JOURNAL OF NEUROSCIENCE
(2020)
Article
Neurosciences
Baris Alten, Qiangjun Zhou, Ok-Ho Shin, Luis Esquivies, Pei-Yi Lin, K. Ian White, Ron Sun, Wendy K. Chung, Lisa M. Monteggia, Axel T. Brunger, Ege T. Kavalali
Summary: Recent studies have shown that mutations in the SNAP25 gene may cause developmental and epileptic encephalopathies, but the specific mechanisms are not yet clear. Research has found that mutations in SNAP25 can lead to related synaptic transmission phenotypes, but specific alterations in spontaneous neurotransmitter release are key factors in disease heterogeneity.
Article
Neurosciences
Wen-Hsin Lu, Hsu-Wen Chao, Pei-Yi Lin, Shu-Hui Lin, Tzu-Hsien Liu, Hao-Wen Chen, Yi-Shuian Huang
Summary: The study shows that CPEB3, as a potential PTSD-risk gene, downregulates Nr3c1 translation to maintain proper GR-BDNF signaling for fear extinction. This highlights the importance of synaptic plasticity and mRNA translation in susceptibility to PTSD-like behavior.
NEUROPSYCHOPHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Xuchen Zhang, Pei-Yi Lin, Kif Liakath-Ali, Thomas C. Sudhof
Summary: Teneurins on the presynaptic side are essential for establishing synaptic connections, and Teneurin-3 assembles into presynaptic nanoclusters in excitatory synapses of the hippocampus. The study demonstrates that Teneurin-3 and Teneurin-4 are required for the assembly of specific synapses in the medial entorhinal cortex.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Burak Uzay, Aiden Houcek, Z. Zack Ma, Christine Konradi, Lisa M. Monteggia, Ege T. Kavalali
Summary: The rapid release of neurotransmitters in synapses is considered an important property, but as synapses mature and age, the release becomes progressively desynchronized. This is caused by NMDAR-mediated transmission leading to ER stress and downregulation of key presynaptic molecules. The emergence of asynchronous release is maintained by synaptotagmin-7 and can be suppressed by GABAergic transmission, inhibition of NMDARs, and ER stress. Long-term disruption of the excitation-inhibition balance affects the synchrony of excitatory neurotransmission in human synapses.
Article
Multidisciplinary Sciences
Pei-Yi Lin, Lulu Y. Chen, Man Jiang, Justin H. Trotter, Erica Seigneur, Thomas C. Sudhof
Summary: Contrary to neurexin-1 and neurexin-3, neurexin-2 restricts synapse formation in the hippocampus. Deleting neurexin-2 increases the strength and release probability of excitatory synapses, while having no effect on inhibitory synapses. Superresolution microscopy reveals that the deletion of neuron-specific neurexin-2 doubles the density of excitatory synapses in the CA1 region.
Article
Multidisciplinary Sciences
Pei-Yi Lin, Lulu Y. Chen, Peng Zhou, Sung-Jin Lee, Justin H. Trotter, Thomas C. Suedhof
Summary: Recent research has shown that the deletion of Nrxn2 unexpectedly leads to an increase in excitatory synapse numbers and their presynaptic release probability, suggesting a role of Nrxn2 in restricting synapse assembly. Cultured hippocampal neurons have been used to study the synaptic function and mechanism of Nrxn2, revealing that certain splice variants of Nrxn2 restrict synapse numbers and restrain their release probability. These findings are significant for understanding the mechanism of synapse assembly.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
