Estradiol Targets Synaptic Proteins to Induce Glutamatergic Synapse Formation in Cultured Hippocampal Neurons: Critical Role of Estrogen Receptor-

AbstractOxytocin contributes to the regulation of cytoskeletal and synaptic proteins and could therefore affect the mechanisms of neurodevelopmental disorders, including autism. Both the Prader-Willi syndrome and Schaaf-Yang syndrome exhibit autistic symptoms involving the MAGEL2 gene. Magel2-deficient mice show a deficit in social behavior that is rescued following postnatal administration of oxytocin. Here, in Magel2-deficient mice, we showed that the neurite outgrowth of primary cultures of immature hippocampal neurons is reduced. Treatment with oxytocin, but not retinoic acid, reversed this abnormality. In the hippocampus of Magel2-deficient pups, we further demonstrated that several transcripts of neurite outgrowth-associated proteins, synaptic vesicle proteins, and cell-adhesion molecules are decreased. In the juvenile stage, when neurons are mature, normalization or even overexpression of most of these markers was observed, suggesting a delay in the neuronal maturation of Magel2-deficient pups. Moreover, we found reduced transcripts of the excitatory postsynaptic marker, Psd95 in the hippocampus and we observed a decrease of PSD95/VGLUT2 colocalization in the hippocampal CA1 and CA3 regions in Magel2-deficient mice, indicating a defect in glutamatergic synapses. Postnatal administration of oxytocin upregulated postsynaptic transcripts in pups; however, it did not restore the level of markers of glutamatergic synapses in Magel2-deficient mice. Overall, Magel2 deficiency leads to abnormal neurite outgrowth and reduced glutamatergic synapses during development, suggesting abnormal neuronal maturation. Oxytocin stimulates the expression of numerous genes involved in neurite outgrowth and synapse formation in early development stages. Postnatal oxytocin administration has a strong effect in development that should be considered for certain neuropsychiatric conditions in infancy.

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Critical role of estrogen receptor on anoikis and invasion of squamous cell carcinoma

Cancer Science ◽

10.1111/j.1349-7006.2007.00437.x ◽

2007 ◽

Vol 98 (5) ◽

pp. 636-643 ◽

Cited By ~ 29

Author(s):

Hiroyuki Ishida ◽

Koichiro Wada ◽

Tomotake Masuda ◽

Masaya Okura ◽

Keiko Kohama ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Estrogen Receptor ◽

Cell Carcinoma ◽

Squamous Cell ◽

Critical Role

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Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons

Journal of Neuroscience Research ◽

10.1002/(sici)1097-4547(19980115)51:2<185::aid-jnr7>3.0.co;2-9 ◽

1998 ◽

Vol 51 (2) ◽

pp. 185-195 ◽

Cited By ~ 48

Author(s):

Takako Morimoto ◽

Ikuroh Ohsawa ◽

Chizuko Takamura ◽

Mariko Ishiguro ◽

Shinichi Kohsaka

Keyword(s):

Amyloid Precursor Protein ◽

Hippocampal Neurons ◽

Synapse Formation ◽

Precursor Protein ◽

Cultured Hippocampal Neurons

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Role of Presynaptic L-Type Ca2+ Channels in GABAergic Synaptic Transmission in Cultured Hippocampal Neurons

Journal of Neurophysiology ◽

10.1152/jn.1999.81.3.1225 ◽

1999 ◽

Vol 81 (3) ◽

pp. 1225-1230 ◽

Cited By ~ 35

Author(s):

Kimmo Jensen ◽

Morten Skovgaard Jensen ◽

John D. C. Lambert

Keyword(s):

Synaptic Transmission ◽

Transmitter Release ◽

Hippocampal Neurons ◽

Low Frequency ◽

Tetanic Stimulation ◽

Vesicle Release ◽

Gabaergic Synaptic Transmission ◽

Cultured Hippocampal Neurons ◽

40 Hz

Role of presynaptic L-type Ca2+ channels in GABAergic synaptic transmission in cultured hippocampal neurons. Using dual whole cell patch-clamp recordings of monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons, we have previously demonstrated posttetanic potentiation (PTP) of IPSCs. Tetanic stimulation of the GABAergic neuron leads to accumulation of Ca2+ in the presynaptic terminals. This enhances the probability of GABA-vesicle release for up to 1 min, which underlies PTP. In the present study, we have examined the effect of altering the probability of release on PTP of IPSCs. Baclofen (10 μM), which depresses presynaptic Ca2+ entry through N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs), caused a threefold greater enhancement of PTP than did reducing [Ca2+]o to 1.2 mM, which causes a nonspecific reduction in Ca2+ entry. This finding prompted us to investigate whether presynaptic L-type VDCCs contribute to the Ca2+ accumulation in the boutons during spike activity. The L-type VDCC antagonist, nifedipine (10 μM), had no effect on single IPSCs evoked at 0.2 Hz but reduced the PTP evoked by a train of 40 Hz for 2 s by 60%. Another L-type VDCC antagonist, isradipine (5 μM), similarly inhibited PTP by 65%. Both L-type VDCC blockers also depressed IPSCs during the stimulation (i.e., they increased tetanic depression). The L-type VDCC “agonist” (−)BayK 8644 (4 μM) had no effect on PTP evoked by a train of 40 Hz for 2 s, which probably saturated the PTP process, but enhanced PTP evoked by a train of 1 s by 91%. In conclusion, the results indicate that L-type VDCCs do not participate in low-frequency synchronous transmitter release, but contribute to presynaptic Ca2+ accumulation during high-frequency activity. This helps maintain vesicle release during tetanic stimulation and also enhances the probability of transmitter release during the posttetanic period, which is manifest as PTP. Involvement of L-type channels in these processes represents a novel presynaptic regulatory mechanism at fast CNS synapses.

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Right Place at the Right Time: How Changes in Protocadherins Affect Synaptic Connections Contributing to the Etiology of Neurodevelopmental Disorders

Cells ◽

10.3390/cells9122711 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2711

Author(s):

Maria Mancini ◽

Silvia Bassani ◽

Maria Passafaro

Keyword(s):

Cell Adhesion ◽

Neurodevelopmental Disorders ◽

Synapse Formation ◽

Large Fraction ◽

Critical Role ◽

Basic Research ◽

Axon Pathfinding ◽

Neurite Initiation ◽

The Right

During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities and impairments collectively referred to as neurodevelopmental disorders. Cell adhesion molecules (CAMs), present on the cell surface, take part in the neurodevelopmental process regulating migration and recognition of specific cells to form functional neuronal assemblies. Among CAMs, the members of the protocadherin (PCDH) group stand out because they are involved in cell adhesion, neurite initiation and outgrowth, axon pathfinding and fasciculation, and synapse formation and stabilization. Given the critical role of these macromolecules in the major neurodevelopmental processes, it is not surprising that clinical and basic research in the past two decades has identified several PCDH genes as responsible for a large fraction of neurodevelopmental disorders. In the present article, we review these findings with a focus on the non-clustered PCDH sub-group, discussing the proteins implicated in the main neurodevelopmental disorders.

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TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

Neural Plasticity ◽

10.1155/2016/4258171 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Valerie T. Ramírez ◽

Eva Ramos-Fernández ◽

Nibaldo C. Inestrosa

Keyword(s):

Protein Kinase ◽

Dendritic Spine ◽

Hippocampal Neurons ◽

Biological Effects ◽

Critical Role ◽

Head Width ◽

Dependent Manner ◽

Spine Density ◽

Dendritic Spine Density

Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator ofPertussis toxin-(PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner. Additionally, Mas-7 enhances postsynaptic density protein-95 (PSD-95) clustering in neurites and activatesGαosignaling, increasing the intracellular Ca2+concentration. To define the role of signaling intermediates, we measured the levels of phosphorylated protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and calcium-calmodulin dependent protein kinase IIα(CaMKIIα) after Mas-7 treatment and determined that CaMKII activation is necessary for the Mas-7-dependent increase in dendritic spine density. Our results demonstrate a critical role forGαosubunit signaling in the regulation of synapse formation.

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L-type Ca2+ channel–mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions

Science Signaling ◽

10.1126/scisignal.aaw6923 ◽

2020 ◽

Vol 13 (618) ◽

pp. eaaw6923 ◽

Cited By ~ 3

Author(s):

Matej Hotka ◽

Michal Cagalinec ◽

Karlheinz Hilber ◽

Livia Hool ◽

Stefan Boehm ◽

...

Keyword(s):

Nitric Oxide ◽

Atp Synthase ◽

Mitochondrial Function ◽

Hippocampal Neurons ◽

Mitochondrial Depolarization ◽

Voltage Gated ◽

Beneficial Effects ◽

Reverse Mode ◽

Cultured Hippocampal Neurons

L-type voltage-gated Ca2+ channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca2+ influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability. Hence, we investigated the effect of modulating LTCC-mediated Ca2+ influx on mitochondrial function in cultured hippocampal neurons. To activate LTCCs, neuronal activity was stimulated by increasing extracellular K+ or by application of the GABAA receptor antagonist bicuculline. The activity of LTCCs was altered by application of an agonistic (Bay K8644) or an antagonistic (isradipine) dihydropyridine. Our results demonstrated that activation of LTCC-mediated Ca2+ influx affected mitochondrial function in a bimodal manner. At moderate stimulation strength, ATP synthase activity was enhanced, an effect that involved Ca2+-induced Ca2+ release from intracellular stores. In contrast, high LTCC-mediated Ca2+ loads led to a switch in ATP synthase activity to reverse-mode operation. This effect, which required nitric oxide, helped to prevent mitochondrial depolarization and sustained increases in mitochondrial Ca2+. Our findings indicate a complex role of LTCC-mediated Ca2+ influx in the tuning and maintenance of mitochondrial function. Therefore, the use of LTCC inhibitors to protect neurons from neurodegeneration should be reconsidered carefully.

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Molecular mechanisms of estrogen receptor β-induced apoptosis and autophagy in tumors: implication for treating osteosarcoma

Journal of International Medical Research ◽

10.1177/0300060519871373 ◽

2019 ◽

Vol 47 (10) ◽

pp. 4644-4655

Author(s):

Zheng-ming Yang ◽

Min-fei Yang ◽

Wei Yu ◽

Hui-min Tao

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptors ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Critical Role ◽

Osteosarcoma Cells ◽

Proliferation And Metastasis ◽

Induced Apoptosis

The estrogen receptors α (ERα) and β (ERβ) are located in the nucleus and bind to estrogen to initiate transcription of estrogen-responsive genes. In a variety of tumor cells, ERβ has been shown to be a tumor suppressor. In particular, ERβ has anti-proliferative effects in osteosarcoma cells. Additionally, ERβ has been proven to regulate the apoptosis-related molecules IAP, BAX, caspase-3, and PARP, and to act on the NF-κB/BCL-2 pathway to induce apoptosis in tumors. Moreover, ERβ can regulate the expression of the autophagy associated markers LC3-I/LC-3II and p62 and induce autophagy in tumors by inhibiting the PI3K/AKT/mTOR pathway and activating the AMPK pathway. Here, we review the molecular mechanisms by which ERβ induces apoptosis and autophagy in a variety of tumors to further delineate more specific molecular mechanisms underlying osteosarcoma tumorigenesis and pathogenesis. Considering the broad involvement of ERβ in apoptosis, autophagy, and their interaction, it is plausible that the critical role of ERβ in inhibiting the proliferation and metastasis of osteosarcoma cells is closely related to its regulation of apoptosis and autophagy.

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