Orchiectomy and letrozole differentially regulate synaptic plasticity and spatial memory in a manner that is mediated by SRC-1 in the hippocampus of male mice

Zhao, Jingming; Bian, Chen; Liu, Mengying; Zhao, Yangang; Sun, Tao; Xing, Fang-Zhou; Zhang, Jiqiang

doi:10.1016/j.jsbmb.2018.02.007

Cited by 42 publications

(35 citation statements)

References 75 publications

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“…The reason for this discrepancy between our findings and theirs is unclear. However, another group that used a twofold higher dose of letrozole did find a significant loss of dendritic spines and synapses in the hippocampus of male mice (Zhao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Neuron-Derived Estrogen Regulates Synaptic Plasticity and Memory

Sareddy²,

et al. 2019

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17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70–80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenous in vivo E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, in vitro studies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatment in vitro . Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain. SIGNIFICANCE STATEMENT The steroid hormone 17β-estradiol (E2) is well known to be produced in the ovaries in females. Intriguingly, forebrain neurons also express aromatase, the E2 biosynthetic enzyme, but the precise functions of neuron-derived E2 is unclear. Using a novel forebrain-neuron-specific aromatase knock-out mouse model to deplete neuron-derived E2, the current study provides direct genetic evidence of a critical role for neuron-derived E2 in the regulation of rapid AKT-ERK and CREB-BDNF signaling in the mouse forebrain and demonstrates that neuron-derived E2 is essential for normal expression of LTP, synaptic plasticity, and cognitive function in both the male and female brain. These findings suggest that neuron-derived E2 functions as a novel neuromodulator in the forebrain to control synaptic plasticity and cognitive function.

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Section: Discussionmentioning

confidence: 99%

Neuron-Derived Estrogen Regulates Synaptic Plasticity and Memory

Sareddy²,

et al. 2019

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“…WB was carried out as described by Zhao et al (2018) and Sun et al (2019a). On the second day after the NOR task, the hippocampus was quickly removed from four groups of mice (n = 3).…”

Section: Western Blotmentioning

confidence: 99%

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate Aβ42 Burden at the Early Stage of Alzheimer’s Disease in APP/PS1 Transgenic Mice

Luo

Yang

et al. 2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease. Intervention in the early stage of AD is a new path for AD treatment that is being explored. The behavioral and pathological effects of anodal transcranial direct current stimulation (AtDCS) at the early stage of AD in the mouse model, amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, were investigated based on our previous studies. Thirty-three 6-month-old male APP/PS1 mice were randomly divided into the model group (AD group), model + sham stimulation group (ADST group) and stimulation group (ADT group). Eleven 6-month-old male C57 wild-type mice were randomly selected as a control group (CTL group). The ADT group received 10 AtDCS sessions. The Morris water maze (MWM) task and novel object recognition (NOR) task were used to test mouse memory. Nissl staining, Western blot (WB), immunohistochemistry and immunofluorescence staining of β-amyloid (Aβ 42), glial fibrillary acidic protein (GFAP) and NF200 were conducted for pathological analysis. The ADT group and the CTL group had a shorter escape latency and more platform-region crossings than the AD group and ADST group in the MWM. There was no significant difference in the discrimination index among the groups in the NOR task. Pathological analysis showed visible differences between the AD group and ADT group. This study revealed that earlystage APP/PS1 transgenic mice did not show recognition memory impairment. AtDCS effectively improved spatial learning and memory in the early-stage APP/PS1 transgenic mouse model of AD, alleviating Aβ burden and having a protective effect on neurons. AtDCS could improve AD-related symptoms by activating many glial cells to promote the degradation and clearance of Aβ or directly affecting production and degradation of Aβ to reduce glial activation. AtDCS is an effective means of early intervention in the early stage of AD.

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“…Furthermore, a recent study has shown that SRC-1 is highly expressed in the hippocampus, and hippocampal SRC-1 knockdown mediated by the lentivirus could cause decreased synaptic protein expression and memory impairment (Bian et al, 2018;Chen et al, 2020). On the other hand, the ER regulates the synaptic protein expression, such as PSD95 and Synapsin, and the cognitive function through the SRC-1-dependent pathway (Liu et al, 2015;Zhao et al, 2017Zhao et al, , 2018. This evidence suggests that SRC-1 is implicated in the cognitive function under the physiological condition and might even play a role in brain disorders with defects of cognition.…”

Section: Discussionmentioning

confidence: 99%

SRC-1 Knockout Exerts No Effect on Amyloid β Deposition in APP/PS1 Mice

Wang

et al. 2020

Front. Aging Neurosci.

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Steroid receptor coactivator 1 (SRC-1) is the key coactivator because of its transcriptional activity. Previous studies have shown that SRC-1 is abundant in the hippocampus and has been implicated in cognition. SRC-1 is also related to some major risk factors for Alzheimer's disease (AD), such as a decline in estrogen and aging, however, whether SRC-1 is involved in the pathogenesis of AD remains unclear. In this study, we established SRC-1 knockout in AD mice by cross breeding SRC-1 −/− mutant mice with APP/PS1 transgenic mice, and investigated the expression of some synaptic proteins, the amyloid β (Aβ) deposition, and activation of astrocytes and microglia in the hippocampus of APP/PS1×SRC-1 −/− mice. The results showed that SRC-1 knockout neither affects the Aβ plaque and activation of glia, nor changes the expression of synaptic proteins in AD model mice. The above results suggest that the complete deletion of SRC-1 in the embryo exerts no effect on the pathogenesis of APP/PS1 mice. Nevertheless, this study could not eliminate the possible role of SRC-1 in the development of AD due to the lack of observation of other events in AD such as tau hyperphosphorylation and the limitation of the animal model employed.

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Orchiectomy and letrozole differentially regulate synaptic plasticity and spatial memory in a manner that is mediated by SRC-1 in the hippocampus of male mice

Cited by 42 publications

References 75 publications

Neuron-Derived Estrogen Regulates Synaptic Plasticity and Memory

Neuron-Derived Estrogen Regulates Synaptic Plasticity and Memory

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate Aβ42 Burden at the Early Stage of Alzheimer’s Disease in APP/PS1 Transgenic Mice

SRC-1 Knockout Exerts No Effect on Amyloid β Deposition in APP/PS1 Mice

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