Hippocampal BMP signaling as a common pathway for antidepressant action

Tunc-Ozcan, Elif; Brooker, Sarah M.; Bonds, Jacqueline A.; Tsai, Yung-Hsu; Rawat, Radhika; McGuire, Tammy L.; Peng, Chian‐Yu; Kessler, John A.

doi:10.1007/s00018-021-04026-y

Cited by 5 publications

(3 citation statements)

References 67 publications

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“…Additionally, there is a parallel decrease in hippocampal neurogenesis during aging and this process has been shown to be negatively regulated by the BMP signaling pathway which is increased during normal aging. Several prior studies have shown that this signaling pathway negatively regulates hippocampus-dependent cognitive functions as well as hippocampal neurogenesis ( Bonaguidi et al, 2008 ; Gobeske et al, 2009 ; Bond et al, 2014 ; Yousef et al, 2015 ; Brooker et al, 2017 ; Tunc-Ozcan et al, 2019 , 2021 ). Thus, the current study aimed to investigate whether varying levels of BMP signaling in the hippocampus could be used as a predictor of cognitive performance in the normal aging process.…”

Section: Discussionmentioning

confidence: 99%

“…A strong candidate signaling pathway was the bone morphogenetic protein (BMP) pathway because of the substantial amount of data supporting its role as a critical regulator of hippocampal neurogenesis and spatial memory function ( Bond et al, 2012 ; Fares et al, 2019 ). Increased levels of BMP signaling suppress the generation of adult-born neurons in the DG and impair performance in hippocampus-dependent cognitive tests, as well as anxiety-like behaviors ( Gobeske et al, 2009 ; Bond et al, 2014 ; Yousef et al, 2015 ; Meyers et al, 2016 ; Tunc-Ozcan et al, 2019 , 2021 ). Specifically, levels of BMP4 have been shown by our group, and many others, to have robust changes with age in the hippocampus of mice ( Yousef et al, 2015 ; Meyers et al, 2016 ; Díaz-Moreno et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition

Bonds

Tunc-Ozcan

Dunlop

et al. 2023

eNeuro

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Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of micro-dissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphometric protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling. Further, cognitive performance was impaired when the BMP inhibitor, noggin, was knocked down in the DG. Infusion of noggin into the lateral ventricles enhanced DG-dependent cognition while BMP4 infusion led to significant impairments. Embryonic overexpression of noggin resulted in lifelong enhancement of recognition and spatial memory while overexpression of BMP4 resulted in lifelong impairment, substantiating the importance of differences in BMP signaling in wildtype mice. These findings indicate that performance in DG-dependent cognitive tasks is largely determined by differences in levels BMP signaling in the dentate gyrus.Significance StatementThroughout life, the generation of new neurons in the brain, or neurogenesis, are known to be important for helping to maintain cognitive abilities. The current study describes a significant mechanism contributing to the changes in neurogenesis in aging and provides a specific molecular target for intervention for aging-related changes in cognitive function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition

Bonds

Tunc-Ozcan

Dunlop

et al. 2023

eNeuro

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“…DBS has been reported to be used to treat several neurobehavioral disorders such as chronic pain, major depression, Tourette’s Syndrome, addiction, obsessive–compulsive disorder and epilepsy, etc., and is mainly applied to patients with PD symptoms. Although, up to now, its potential molecular and physiological mechanism is still unknown, it has been reported that DBS may act via a few mechanisms including the electrical and neurochemical effects of stimulation in the network, the modulation of oscillatory activity and synaptic plasticity, and, potentially, neuroprotection and neurogenesis, either directly, or by modulating the circuitry or signaling pathways [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. LID remains a significant problem in patients with PD, which has a significant negative impact on health-related quality of life and health economic outcomes [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Retrospective Multicenter Study on Outcome Measurement for Dyskinesia Improvement in Parkinson’s Disease Patients with Pallidal and Subthalamic Nucleus Deep Brain Stimulation

Meng

Cen

et al. 2022

Brain Sciences

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Deep brain stimulation (DBS) is an effective treatment for dyskinesia in patients with Parkinson’s disease (PD), among which the therapeutic targets commonly used include the subthalamic nucleus (STN) and the globus pallidus internus (GPi). Levodopa-induced dyskinesia (LID) is one of the common motor complications arising in PD patients on chronic treatment with levodopa. In this article, we retrospectively evaluated the outcomes of LID with the Unified Dyskinesia Rating Scale (UDysRS) in patients who underwent DBS in multiple centers with a GPi or an STN target. Meanwhile, the Med off MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-Ⅲ) and the levodopa equivalent daily dose (LEDD) were also observed as secondary indicators. PD patients with a GPi target showed a more significant improvement in the UDysRS compared with an STN target (92.9 ± 16.7% vs. 66.0 ± 33.6%, p < 0.0001). Both the GPi and the STN showed similar improvement in Med off UPDRS-III scores (49.8 ± 22.6% vs. 52.3 ± 29.5%, p = 0.5458). However, the LEDD was obviously reduced with the STN target compared with the GPi target (44.6 ± 28.1% vs. 12.2 ± 45.8%, p = 0.006).

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Ketamine’s rapid and sustained antidepressant effects are driven by distinct mechanisms

Rawat,

Tunc-Ozcan,

Dunlop

et al. 2024

Cell. Mol. Life Sci.

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Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine’s rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine’s rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained – but not the rapid – behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine’s sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine’s sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine’s dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.

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Hippocampal BMP signaling as a common pathway for antidepressant action

Cited by 5 publications

References 67 publications

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition

Retrospective Multicenter Study on Outcome Measurement for Dyskinesia Improvement in Parkinson’s Disease Patients with Pallidal and Subthalamic Nucleus Deep Brain Stimulation

Ketamine’s rapid and sustained antidepressant effects are driven by distinct mechanisms

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