Effects and Mechanisms of Synaptotagmin-7 in the Hippocampus on Cognitive Impairment in Aging Mice

Xie, Yunxuan; Zhi, Kaining; Meng, Xianhong

doi:10.1007/s12035-021-02528-1

Cited by 10 publications

(4 citation statements)

References 44 publications

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“…We have shown that Syt7 plays a predominant role in phasic somatodendritic DA release, with substitution by Syt1 when Syt7 is absent, and that Syt1 plays a predominant role in tonic somatodendritic DA release. Intriguingly, Syt7 has been identified as a candidate risk factor for behavioral abnormalities in bipolar disorder and cognitive impairment in Alzheimer's disease (Barthet et al, 2018;Shen et al, 2020;Xie et al, 2021), whereas Syt1 has been associated with neurologic deficits, including movement and neurodevelopmental disorders (Baker et al, 2015(Baker et al, , 2018. These effects could reflect in part altered DA neuron regulation through the roles of Syt7 and Syt1 identified here, extending the potential importance of the findings.…”

Section: Discussionsupporting

confidence: 66%

Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

et al. 2022

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The molecular mechanisms underlying somatodendritic dopamine (DA) release remain unresolved, despite the passing of decades since its discovery. Our previous work showed robust release of somatodendritic DA in submillimolar extracellular Ca 21 concentration ([Ca 21 ] o ). Here we tested the hypothesis that the high-affinity Ca 21 sensor synaptotagmin 7 (Syt7), is a key determinant of somatodendritic DA release and its Ca 21 dependence. Somatodendritic DA release from SNc DA neurons was assessed using whole-cell recording in midbrain slices from male and female mice to monitor evoked DA-dependent D2 receptor-mediated inhibitory currents (D2ICs). Single-cell application of an antibody to Syt7 (Syt7 Ab) decreased pulse trainevoked D2ICs, revealing a functional role for Syt7. The assessment of the Ca 21 dependence of pulse train-evoked D2ICs confirmed robust DA release in submillimolar [Ca 21 ] o in wild-type (WT) neurons, but loss of this sensitivity with intracellular Syt7 Ab or in Syt7 knock-out (KO) mice. In millimolar [Ca 21 ] o , pulse train-evoked D2ICs in Syt7 KOs showed a greater reduction in decreased [Ca 21 ] o than seen in WT mice; the effect on single pulse-evoked DA release, however, did not differ between genotypes. Single-cell application of a Syt1 Ab had no effect on train-evoked D2ICs in WT SNc DA neurons, but did cause a decrease in D2IC amplitude in Syt7 KOs, indicating a functional substitution of Syt1 for Syt7. In addition, Syt1 Ab decreased single pulse-evoked D2ICs in WT cells, indicating the involvement of Syt1 in tonic DA release. Thus, Syt7 and Syt1 play complementary roles in somatodendritic DA release from SNc DA neurons.

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Section: Discussionsupporting

confidence: 66%

Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

et al. 2022

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“…Male C57BL/6J mice at the age of 7–8 weeks were anesthetized by intraperitoneal injection of pentobarbital (60 mg/kg body weight) and then placed on a stereotaxic apparatus (68,030, RWD Life Science, China) as previously described ( Xie et al, 2021 ). Briefly, control (AAV8-enhanced green fluorescent protein [eGFP]) or MAD2B-overexpressing adeno-associated virus 8 (AAV8-MAD2B-OE-eGFP) was injected into the hippocampus (coordinates: AP −2.0 mm, ML 2.68 mm, DV 1.68 mm from the bregma).…”

Section: Methodsmentioning

confidence: 99%

“…Western-blot analysis was conducted as previously described ( Xie et al, 2021 ). Total protein was extracted from mouse hippocampi or cultured neurons using RIPA lysis buffer (Beyotime, Shanghai, China) with phenylmethylsulfonyl fluoride.…”

Section: Methodsmentioning

confidence: 99%

MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation–Induced Depression-Like Behaviors in Mice

Wang

Cheng

et al. 2022

International Journal of Neuropsychopharmacology

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Background Depression is a prevalent and recurrent psychiatric disorder. Aberrant neural structure and activity play fundamental roles in the occurrence of depression. Mitotic arrest deficient protein (MAD2B) is highly expressed in neurons and may be implicated in synaptic plasticity in the central nervous system. However, the effect of MAD2B in depression, as well as the related molecular mechanism, is uncertain. Methods Here, we employed mouse models of depression induced by chronic unpredictable stress (CUS) exposure or corticosterone (CORT) stimulation. Depression-like behaviors in mice were evaluated by sucrose preference, forced swimming, and tail suspension tests. Hippocampal MAD2B overexpression was mediated by adeno-associated virus 8 containing eGFP. In vitro, primary neuronal cells were obtained from the hippocampus of rat embryos and were treated with CORT; while MAD2B overexpression was performed using lentivirus. MAD2B and glutamate metabotropic receptor 4 (GRM4) levels were evaluated by Western blots and qPCR. Primary neuronal miR-29b-3p expression was detected by qPCR. Results MAD2B expression was reduced in the hippocampus in mice exhibiting depressive-like behaviors. However, hippocampal MAD2B overexpression protected mice from developing either CUS- or CORT-induced depression-like behaviors, an effect associated with reduced expression of GRM4, a presynaptic receptor involved in depression. Moreover, MAD2B overexpression in primary neuronal cells also decreased GRM4 expression while enhancing the level of miR-29b-3p; this phenomenon was also observed under CORT stimulation. Conclusions Our results suggest an important role of neuronal MAD2B in the pathogenesis of depression via the miR-29b-3p/ GRM4 signaling pathway. MAD2B could be a potential therapeutic target for depressive disorders.

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“…Notably, synaptotagmin-1 (Syt-1) displays low Ca 2+ affinity and is needed for synchronous neurotransmitter release [45,46], while synaptotagmin-7 (Syt-7) displays high calcium affinity and functions as a Ca 2+ sensor to trigger synaptic vesicle fusion with plasma membrane at conditions of low Ca 2+ concentrations [47][48][49]. Experimental data suggests that Syt-7 plays a significant role in asynchronous neurotransmitter release that occurs during repetitive synaptic activation [45,50] and significantly contributes to synaptic facilitation [51][52][53][54][55] and normal brain function [56,57]. Notably, Syt-7 may facilitate neurotransmitter release during the period that follows an action potential in the presynaptic terminal, by effectively sensing the low levels of Ca 2+ during this period [58].…”

Section: Introductionmentioning

confidence: 99%

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in Male and Female Hippocampus of a Rat Model of Fragile X Syndrome

Tsotsokou,

Miliou,

Trompoukis

et al. 2024

Preprint

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Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in short-term processing of neural information such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to a crucial involvement of presynaptic calcium sensor synaptotagmin-7 in STSP. However, how the loss of FMRP affects STSP and synaptotagmin-7 have been insufficiently studied. Further-more, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study is to investigate possible changes in STSP and the expres-sion of synaptotagmin-7 along the hippocampus of adult males and females in the Fmr1 knock-out (KO) rat model of FXS. We found that paired-pulse ratio and frequency facilita-tion/depression, two forms of STSP, as well as the expression of synaptotagmin-7, are normal in adult KO males, but paired-pulse ratio is increased in the ventral hippocampus of KO females. Furthermore, we found no gender-related but robust region-dependent difference in STSP. AM-PA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared with females. Interestingly, we found more than twofold higher levels of synaptotagmin-7, not syn-aptotagmin-1, in the dorsal compared with the ventral hippocampus in males of both genotypes and in wild type females. These results point to the susceptibility of the female ventral hippo-campus to FMRP loss. Importantly, the different levels of synaptotagmin-7 that parallel the higher score of synaptic facilitation in the dorsal vs ventral hippocampus suggest that synapto-tagmin-7 may play a pivotal role in defining the striking difference in STSP along the long axis of the hippocampus.

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Effects and Mechanisms of Synaptotagmin-7 in the Hippocampus on Cognitive Impairment in Aging Mice

Cited by 10 publications

References 44 publications

Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

Synaptotagmins 1 and 7 Play Complementary Roles in Somatodendritic Dopamine Release

MAD2B Blunts Chronic Unpredictable Stress and Corticosterone Stimulation–Induced Depression-Like Behaviors in Mice

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in Male and Female Hippocampus of a Rat Model of Fragile X Syndrome

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