5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.

doi:10.3389/fnbeh.2014.00391

Cited by 24 publications

(21 citation statements)

References 49 publications

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“…Transactivation of TrkB, in the absence of BDNF, has been described for several treatments including 5-HT (Samarajeewa et al, 2014), epidermal growth factor (Puehringer et al, 2013), antidepressant drugs (Rantamaki et al, 2011), and adenosine (Rajagopal and Chao, 2006).…”

Section: Discussionmentioning

confidence: 99%

Estrogen’s Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function

Wang

Kantorovich

Babayan

et al. 2016

Neuropsychopharmacol

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Estradiol (E2) perfusion rapidly increases the strength of fast excitatory transmission and facilitates long-term potentiation in the hippocampus, two effects likely related to its memory-enhancing properties. Past studies showed that E2's facilitation of transmission involves activation of RhoA signaling leading to actin polymerization in dendritic spines. Here we report that brief exposure of adult male hippocampal slices to 1 nM E2 increases the percentage of postsynaptic densities associated with high levels of immunoreactivity for activated forms of the BDNF receptor TrkB and β1-integrins, two synaptic receptors that engage actin regulatory RhoA signaling. The effects of E2 on baseline synaptic responses were unaffected by pretreatment with the TrkB-Fc scavenger for extracellular BDNF or TrkB antagonism, but were eliminated by neutralizing antisera for β1-integrins. E2 effects on synaptic responses were also absent in conditional β1-integrin knockouts, and with inhibition of matrix metalloproteinases, extracellular enzymes that generate integrin ligands. We propose that E2, acting through estrogen receptor-β, transactivates synaptic TrkB and β1-integrin, and via mechanisms dependent on integrin activation and signaling, reversibly reorganizes the spine cytoskeleton and thereby enhances synaptic responses in adult hippocampus.

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Section: Discussionmentioning

confidence: 99%

Estrogen’s Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function

Wang

Kantorovich

Babayan

et al. 2016

Neuropsychopharmacol

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“…The BDNF receptor TrkB is a transmembrane proteins of the Trk family of neurotrophin receptors [ 30 ]. TrkB receptors are activated by BDNF-induced formation of receptor dimers, whereupon the dimerized receptors rapidly phosphorylate each other and activate downstream signaling pathways [ 79 – 81 ]. In the current study, the increased spinal expression of TrkB and its subsequent phosphorylation/activation after 7 days of AIH and motor training in SCI rats strongly suggests that the effects of this combined treatment are at least in part mediated by the activation of TrkB signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression

et al. 2018

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One of the most promising approaches to improve recovery after spinal cord injury (SCI) is the augmentation of spontaneously occurring plasticity in uninjured neural pathways. Acute intermittent hypoxia (AIH, brief exposures to reduced O2 levels alternating with normal O2 levels) initiates plasticity in respiratory systems and has been shown to improve recovery in respiratory and non-respiratory spinal systems after SCI in experimental animals and humans. Although the mechanism by which AIH elicits its effects after SCI are not well understood, AIH is known to alter protein expression in spinal neurons in uninjured animals. Here, we examine hypoxia- and plasticity-related protein expression using immunofluorescence in spinal neurons in SCI rats that were treated with AIH combined with motor training, a protocol which has been demonstrated to improve recovery of forelimb function in this lesion model. Specifically, we assessed protein expression in spinal neurons from animals with incomplete cervical SCI which were exposed to AIH treatment + motor training either for 1 or 7 days. AIH treatment consisted of 10 episodes of AIH: (5 min 11% O2: 5 min 21% O2) for 7 days beginning at 4 weeks post-SCI. Both 1 or 7 days of AIH treatment + motor training resulted in significantly increased expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) relative to normoxia-treated controls, in neurons both proximal (cervical) and remote (lumbar) to the SCI. All other markers examined were significantly elevated in the 7 day AIH + motor training group only, at both cervical and lumbar levels. These markers included vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and phosphorylated and nonphosphorylated forms of the BDNF receptor tropomyosin-related kinase B (TrkB). In summary, AIH induces plasticity at the cellular level after SCI by altering the expression of major plasticity- and hypoxia-related proteins at spinal regions proximal and remote to the SCI. These changes occur under the same AIH protocol which resulted in recovery of limb function in this animal model. Thus AIH, which induces plasticity in spinal circuitry, could also be an effective therapy to restore motor function after nervous system injury.

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“…For example, it has recently been reported that treatment with 5-HT 7 receptor agonist can increase the expression and phosphorylation of tropomyosin-related kinase B (TrkB) receptor. 44 TrkB is a receptor of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors that are involved in both neuronal plasticity and remodeling of neuronal morphology. Thus, these findings suggest that the BDNF signaling may be enhanced by 5-HT 7 receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Brain 5-HT7 Receptors in the Formation of Stress Adaptation in Mice

2017

JERP

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Background/Objectives: Impairment of the ability to adapt to stress in animals may contribute to some stressrelated psychiatric disorders, such as anxiety and depression. A growing body of evidence has suggested that the brain's serotonin (5-HT) nervous system may play an important role in the etiology, expression and treatment of anxiety and depression. The aim of the present study was to examine whether brain 5-HT 7 receptors are involved in the formation of stress adaptation. Methods:Male ICR mice were either exposed to repeated restraint stress for 60 or 240 min/day (stressed group) or left in their home cage (non-stressed group) for 1 or 14 days. The emotionality of mice was estimated by the hole-board test. The levels of 5-HT 7 receptor expression and extracellular signal-regulated kinase 1/2 (ERK) phosphorylation were assessed by western blot analysis. Results:A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response was not observed in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. Increases in 5-HT 7 receptor protein and ERK phosphorylation were observed in the frontal cortex and hippocampus of stress-adaptive, but not stress-maladaptive, mice. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with LP-12, a selective 5-HT 7 receptor agonist, immediately after daily exposure to stress. Conclusion:The present findings suggest that the brain 5-HT 7 receptor-ERK system may play an important role in the formation of stress adaptation. Furthermore, stimulation of 5-HT 7 receptors may have a beneficial effect on stress adaptation and alleviate the emotional abnormality observed under conditions of excessive stress.

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5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

Cited by 24 publications

References 49 publications

Estrogen’s Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function

Estrogen’s Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression

Involvement of Brain 5-HT7 Receptors in the Formation of Stress Adaptation in Mice

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