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Article ; Online: Regulation of adult-born and mature neurons in stress response and antidepressant action in the dentate gyrus of the hippocampus.

Segi-Nishida, Eri / Suzuki, Kanzo

2022

Abstract: The dentate gyrus (DG) of the hippocampus has been implicated in the regulation of stress responses, and in the pathophysiology and treatment of depression. This review discusses the cellular changes caused by chronic stress and the cellular role of the ... ...

Abstract	The dentate gyrus (DG) of the hippocampus has been implicated in the regulation of stress responses, and in the pathophysiology and treatment of depression. This review discusses the cellular changes caused by chronic stress and the cellular role of the DG in stress-induced behavioral changes and its antidepressant-like effects. Regarding adult-born neurogenic processes in the DG, chronic stress, such as repeated social defeat, suppresses cell proliferation during and immediately after stress; however, this effect is transient. The subsequent differentiation and survival processes are differentially regulated depending on the timing and sensitivity of stress. The activation of young adult-born neurons during stress contributes to stress resilience, while the transient increase in the survival of adult-born neurons after the cessation of stress seems to promote stress susceptibility. In mature granule neurons, the predominant cells in the DG, synaptic plasticity is suppressed by chronic stress. However, a group of mature granule neurons is activated by chronic stress. Chronic antidepressant treatment can transform mature granule neurons to a phenotype resembling that of immature neurons, characterized as "dematuration". Adult-born neurons suppress the activation of mature granule neurons during stress, indicating that local neural interactions within the DG are important for the stress response. Elucidating the stress-associated context- and timing-dependent cellular changes and functions in the DG will provide insights into stress-related psychiatric diseases.
Language	English
Publishing date	2022-08-27
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	605842-5
ISSN	1872-8111 ; 0168-0102 ; 0921-8696
ISSN (online)	1872-8111
ISSN	0168-0102 ; 0921-8696
DOI	10.1016/j.neures.2022.08.010
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Article ; Online: Ketamine: Mechanisms and Relevance to Treatment of Depression.

Kim, Ji-Woon / Suzuki, Kanzo / Kavalali, Ege T / Monteggia, Lisa M

Annual review of medicine

2023 Volume 75, Page(s) 129–143

Abstract: Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight ... ...

Abstract	Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.
MeSH term(s)	Humans ; Ketamine/therapeutic use ; Depression/drug therapy ; Depressive Disorder, Major/drug therapy ; Antidepressive Agents/therapeutic use ; Amines/therapeutic use
Chemical Substances	Ketamine (690G0D6V8H) ; Antidepressive Agents ; Amines
Language	English
Publishing date	2023-09-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207930-6
ISSN	1545-326X ; 0066-4219
ISSN (online)	1545-326X
ISSN	0066-4219
DOI	10.1146/annurev-med-051322-120608
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Article ; Online: Bridging rapid and sustained antidepressant effects of ketamine.

Kim, Ji-Woon / Suzuki, Kanzo / Kavalali, Ege T / Monteggia, Lisa M

Trends in molecular medicine

2023 Volume 29, Issue 5, Page(s) 364–375

Abstract: Acute administration of (R,S)-ketamine (ketamine) produces rapid antidepressant effects that in some patients can be sustained for several days to more than a week. Ketamine blocks N-methyl-d-asparate (NMDA) receptors (NMDARs) to elicit specific ... ...

Abstract	Acute administration of (R,S)-ketamine (ketamine) produces rapid antidepressant effects that in some patients can be sustained for several days to more than a week. Ketamine blocks N-methyl-d-asparate (NMDA) receptors (NMDARs) to elicit specific downstream signaling that induces a novel form of synaptic plasticity in the hippocampus that has been linked to the rapid antidepressant action. These signaling events lead to subsequent downstream transcriptional changes that are involved in the sustained antidepressant effects. Here we review how ketamine triggers this intracellular signaling pathway to mediate synaptic plasticity which underlies the rapid antidepressant effects and links it to downstream signaling and the sustained antidepressant effects.
MeSH term(s)	Humans ; Ketamine/pharmacology ; Ketamine/therapeutic use ; Ketamine/metabolism ; Depression/drug therapy ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Antidepressive Agents/metabolism ; Hippocampus ; Signal Transduction
Chemical Substances	Ketamine (690G0D6V8H) ; Antidepressive Agents
Language	English
Publishing date	2023-03-10
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2023.02.003
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Article ; Online: Optical analysis of AMPAR-mediated synaptic scaling in mouse hippocampus.

Suzuki, Kanzo / Kavalali, Ege T / Monteggia, Lisa M

STAR protocols

2022 Volume 3, Issue 2, Page(s) 101443

Abstract: Immunolabeling of surface AMPA receptors (AMPARs) can be used ... ...

Abstract	Immunolabeling of surface AMPA receptors (AMPARs) can be used for
MeSH term(s)	Animals ; Hippocampus/diagnostic imaging ; Homeostasis ; Mice ; Receptors, AMPA/metabolism
Chemical Substances	Receptors, AMPA
Language	English
Publishing date	2022-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101443
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Article ; Online: The role of eEF2 kinase in the rapid antidepressant actions of ketamine.

Suzuki, Kanzo / Monteggia, Lisa M

Advances in pharmacology (San Diego, Calif.)

2020 Volume 89, Page(s) 79–99

Abstract: Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed ... ...

Abstract	Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.
MeSH term(s)	Animals ; Antidepressive Agents/pharmacology ; Depression/drug therapy ; Depression/physiopathology ; Elongation Factor 2 Kinase/metabolism ; Humans ; Ketamine/pharmacology ; Ketamine/therapeutic use ; Neuronal Plasticity/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism
Chemical Substances	Antidepressive Agents ; Receptors, N-Methyl-D-Aspartate ; Ketamine (690G0D6V8H) ; Elongation Factor 2 Kinase (EC 2.7.11.20)
Language	English
Publishing date	2020-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	1557-8925
ISSN (online)	1557-8925
DOI	10.1016/bs.apha.2020.04.005
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Article ; Online: Hippocampal Inflammation and Gene Expression Changes in Peripheral Lipopolysaccharide Challenged Mice Showing Sickness and Anxiety-Like Behaviors.

Matsuura, Sumire / Nishimoto, Yuki / Endo, Akane / Shiraki, Hirono / Suzuki, Kanzo / Segi-Nishida, Eri

Biological & pharmaceutical bulletin

2023 Volume 46, Issue 9, Page(s) 1176–1183

Abstract: Neuroinflammation is often associated with the development of depressive and anxiety disorders. The hippocampus is one of the brain regions affected by inflammation that is associated with these symptoms. However, the mechanism of hippocampal ... ...

Abstract	Neuroinflammation is often associated with the development of depressive and anxiety disorders. The hippocampus is one of the brain regions affected by inflammation that is associated with these symptoms. However, the mechanism of hippocampal inflammation-induced emotional behavior remains unknown. The aim of this study was to clarify temporal changes in the neuroinflammatory responses in the hippocampus and the response of dentate gyrus (DG) neurons using peripheral lipopolysaccharide (LPS)-challenged mice. LPS administration induced anxiety-like activity in the elevated plus maze test and social interaction test after 24 h, at which time the mice had recovered from sickness behavior. We examined the hippocampal inflammation-related gene expression changes over time. The expression of interleukin-1β (Il1b) and tumor necrosis factor α (Tnfa) was rapidly enhanced and sustained until 24 h after LPS administration, whereas the expression of Il6 was transiently induced at approx. 6 h. IL-6-dependent downstream signaling of transducer and activator of transcription 3 (STAT3) was also activated approx. 3-6 h after LPS treatment. The expression of innate immune genes including interferon-induced transmembrane proteins such as interferon-induced transmembrane protein 1 (Ifitm1) and Ifitm3 and complement factors such as C1qa and C1qb started to increase approx. 6 h and showed sustained or further increase at 24 h. We also examined changes in the expression of several maturation markers in the DG and found that LPS enhanced the expression of calbindin 1 (Calb1), tryptophan-2,3-dioxigenase 2 (Tdo2), Il1rl, and neurotrophin-3 (Ntf3) at 24 h after LPS treatment. Collectively, these results demonstrate temporal changes of inflammation and gene expression in the hippocampus in LPS-induced sickness and anxiety-like behaviors.
MeSH term(s)	Animals ; Mice ; Lipopolysaccharides/toxicity ; Anxiety/chemically induced ; Anxiety/genetics ; Inflammation/chemically induced ; Inflammation/genetics ; Hippocampus ; Interferons ; Gene Expression
Chemical Substances	Lipopolysaccharides ; Interferons (9008-11-1)
Language	English
Publishing date	2023-09-03
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b22-00729
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Article: Overexpression of NT-3 in the hippocampus suppresses the early phase of the adult neurogenic process.

Kasakura, Nanami / Murata, Yuka / Shindo, Asuka / Kitaoka, Shiho / Furuyashiki, Tomoyuki / Suzuki, Kanzo / Segi-Nishida, Eri

Frontiers in neuroscience

2023 Volume 17, Page(s) 1178555

Abstract: The dentate gyrus (DG) of the hippocampus regulates stress-related emotional behaviors and ensures neurogenesis throughout life. Neurotrophin-3 (NT-3) is a neurotrophic factor that regulates neuronal differentiation, survival, and synaptic formation in ... ...

Abstract	The dentate gyrus (DG) of the hippocampus regulates stress-related emotional behaviors and ensures neurogenesis throughout life. Neurotrophin-3 (NT-3) is a neurotrophic factor that regulates neuronal differentiation, survival, and synaptic formation in both the peripheral and central nervous systems. NT-3 is expressed in the adult DG of the hippocampus; several chronic stress conditions enhance NT-3 expression in rodents. However, functional modulation of the adult DG by NT-3 signaling remains unclear. To directly investigate the impact of NT-3 on DG function, NT-3 was overexpressed in the hippocampal ventral DG by an adeno-associated virus carrying NT-3 (AAV-NT-3). Four weeks following the AAV-NT-3 injection, high NT-3 expression was observed in the ventral DG. We examined the influence of NT-3 overexpression on the neuronal responses and neurogenic processes in the ventral DG. NT-3 overexpression significantly increased the expression of the mature DG neuronal marker calbindin and immediate early genes, such as
Language	English
Publishing date	2023-07-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1178555
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Article: Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against community-acquired pneumonia in older individuals after the introduction of childhood 13-valent pneumococcal conjugate vaccine: A multicenter hospital-based case-control study in Japan

Nakashima, Kei / Suzuki, Kanzo / Aoshima, Masahiro / Murabata, Mayumi / Kondo, Kyoko / Ohfuji, Satoko / Fukushima, Wakaba / Maeda, Akiko / Hirota, Yoshio

Vaccine. 2022 Sept. 17,

2022

Abstract: In the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been reported worldwide. ...

Institution	Pneumonia in Elderly People Study Group
Abstract	In the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been reported worldwide. Therefore, continuous evaluation of the effectiveness of the pneumococcal vaccine in adults is crucial because vaccine effectiveness may change owing to these factors. The purpose of this study was to evaluate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against all-cause pneumonia and pneumococcal pneumonia in older individuals with community-acquired pneumonia (CAP) after the introduction of childhood PCV13 in Japan, a topic that has remained largely unexplored. We evaluated pneumococcal vaccine effectiveness in this multicenter, matched case-control study conducted in hospitals and clinics. Cases included patients (aged ≥ 65 years) newly diagnosed with CAP between October 2016 and September 2019. A maximum of five non-pneumonia control patients matched for sex, school grade, date of outpatient visit, and medical institution were selected for each case. Conditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of pneumococcal vaccines for the occurrence of all-cause CAP and pneumococcal CAP. The analysis included 740 individuals (142 patients and 598 controls). The median age of participants was 75 years (men: 54%). The adjusted OR for pneumococcal vaccination against all-cause CAP was 1.31 (95% CI: 0.84–2.06), while that for PPSV23 vaccination in the previous 5 years was 1.33 (95% CI: 0.85–2.09). The adjusted OR for PPSV23 vaccination in the previous 5 years against pneumococcal CAP was 0.93 (95% CI: 0.35–2.50). This study was unable to demonstrate the effectiveness of PPSV23 against all-cause and pneumococcal pneumonia after the introduction of childhood PCV13 in Japan. Nonetheless, additional studies are needed to validate these results.
Keywords	Japan ; Streptococcus pneumoniae ; case-control studies ; childhood ; herd immunity ; pneumonia ; polysaccharides ; regression analysis ; serotypes ; vaccination ; vaccines
Language	English
Dates of publication	2022-0917
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2022.09.055
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Article ; Online: Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action.

Suzuki, Kanzo / Kim, Ji-Woon / Nosyreva, Elena / Kavalali, Ege T / Monteggia, Lisa M

Cell reports

2021 Volume 37, Issue 5, Page(s) 109918

Abstract: Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid ... ...

Abstract	Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action.
MeSH term(s)	Animals ; Antidepressive Agents/pharmacology ; CA1 Region, Hippocampal/drug effects ; CA1 Region, Hippocampal/metabolism ; Elongation Factor 2 Kinase/genetics ; Elongation Factor 2 Kinase/metabolism ; HEK293 Cells ; Humans ; Ketamine/pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Neuronal Plasticity/drug effects ; Neurons/drug effects ; Neurons/metabolism ; Retinoic Acid Receptor alpha/agonists ; Retinoic Acid Receptor alpha/genetics ; Retinoic Acid Receptor alpha/metabolism ; Synapses/drug effects ; Synapses/metabolism ; Synaptic Transmission/drug effects ; Time Factors ; Tretinoin/pharmacology ; Mice
Chemical Substances	Antidepressive Agents ; Rara protein, mouse ; Retinoic Acid Receptor alpha ; Tretinoin (5688UTC01R) ; Ketamine (690G0D6V8H) ; Eef2k protein, mouse (EC 2.7.11.20) ; Elongation Factor 2 Kinase (EC 2.7.11.20)
Language	English
Publishing date	2021-12-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109918
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Article ; Online: Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against community-acquired pneumonia in older individuals after the introduction of childhood 13-valent pneumococcal conjugate vaccine: A multicenter hospital-based case-control study in Japan.

Nakashima, Kei / Suzuki, Kanzo / Aoshima, Masahiro / Murabata, Mayumi / Kondo, Kyoko / Ohfuji, Satoko / Fukushima, Wakaba / Maeda, Akiko / Hirota, Yoshio

Vaccine

2022 Volume 40, Issue 46, Page(s) 6589–6598

Abstract: Background: In the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been ... ...

Abstract	Background: In the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been reported worldwide. Therefore, continuous evaluation of the effectiveness of the pneumococcal vaccine in adults is crucial because vaccine effectiveness may change owing to these factors. The purpose of this study was to evaluate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against all-cause pneumonia and pneumococcal pneumonia in older individuals with community-acquired pneumonia (CAP) after the introduction of childhood PCV13 in Japan, a topic that has remained largely unexplored. Methods: We evaluated pneumococcal vaccine effectiveness in this multicenter, matched case-control study conducted in hospitals and clinics. Cases included patients (aged ≥ 65 years) newly diagnosed with CAP between October 2016 and September 2019. A maximum of five non-pneumonia control patients matched for sex, school grade, date of outpatient visit, and medical institution were selected for each case. Conditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of pneumococcal vaccines for the occurrence of all-cause CAP and pneumococcal CAP. Results: The analysis included 740 individuals (142 patients and 598 controls). The median age of participants was 75 years (men: 54%). The adjusted OR for pneumococcal vaccination against all-cause CAP was 1.31 (95% CI: 0.84-2.06), while that for PPSV23 vaccination in the previous 5 years was 1.33 (95% CI: 0.85-2.09). The adjusted OR for PPSV23 vaccination in the previous 5 years against pneumococcal CAP was 0.93 (95% CI: 0.35-2.50). Conclusions: This study was unable to demonstrate the effectiveness of PPSV23 against all-cause and pneumococcal pneumonia after the introduction of childhood PCV13 in Japan. Nonetheless, additional studies are needed to validate these results.
MeSH term(s)	Male ; Adult ; Humans ; Aged ; Pneumonia, Pneumococcal/epidemiology ; Pneumonia, Pneumococcal/prevention & control ; Vaccines, Conjugate/therapeutic use ; Case-Control Studies ; Japan/epidemiology ; Pneumococcal Vaccines/therapeutic use ; Streptococcus pneumoniae ; Community-Acquired Infections/epidemiology ; Community-Acquired Infections/prevention & control ; Hospitals ; Pneumococcal Infections/epidemiology ; Pneumococcal Infections/prevention & control
Chemical Substances	23-valent pneumococcal capsular polysaccharide vaccine ; Vaccines, Conjugate ; Pneumococcal Vaccines
Language	English
Publishing date	2022-09-30
Publishing country	Netherlands
Document type	Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2022.09.055
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