Dendritic Excitability and Synaptic Plasticity In Vitro and In Vivo

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

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Regulation of GABAergic synapse formation and plasticity by GSK3β-dependent phosphorylation of gephyrin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1011824108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 379-384 ◽

Cited By ~ 116

Author(s):

Shiva K. Tyagarajan ◽

Himanish Ghosh ◽

Gonzalo E. Yévenes ◽

Irina Nikonenko ◽

Claire Ebeling ◽

...

Keyword(s):

Synaptic Plasticity ◽

Hippocampal Neurons ◽

Glycogen Synthase ◽

Phosphorylation Site ◽

Scaffolding Protein ◽

Scaffolding Proteins ◽

Gabaergic Synapse ◽

Gabaergic Synapses

Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β inhibitor used therapeutically as mood-stabilizing drug, which underscores the relevance of this posttranslational modification for synaptic plasticity. Conversely, we show that gephyrin availability for postsynaptic clustering is limited by Ca2+-dependent gephyrin cleavage by the cysteine protease calpain-1. Together, these findings identify gephyrin as synaptogenic molecule regulating GABAergic synaptic plasticity, likely contributing to the therapeutic action of lithium.

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In Vitro Systems as Simulations of In Vivo Conditions: The Study of Cognition and Synaptic Plasticity in Neurotoxicologya

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2000.tb06874.x ◽

2006 ◽

Vol 919 (1) ◽

pp. 119-132 ◽

Cited By ~ 8

Author(s):

M. E. GILBERT

Keyword(s):

Synaptic Plasticity ◽

In Vitro Systems

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The Amygdaloid Complex: Anatomy and Physiology

Physiological Reviews ◽

10.1152/physrev.00002.2003 ◽

2003 ◽

Vol 83 (3) ◽

pp. 803-834 ◽

Cited By ~ 902

Author(s):

P. SAH ◽

E. S. L. FABER ◽

M. LOPEZ DE ARMENTIA ◽

J. POWER

Keyword(s):

Synaptic Plasticity ◽

Sensory Information ◽

Amygdaloid Complex ◽

In Vivo Studies ◽

Anatomy And Physiology ◽

Efferent Connections ◽

Complex Anatomy ◽

Subcortical Regions

Sah, P., E. S. L. Faber, M. Lopez de Armentia, and J. Power. The Amygdaloid Complex: Anatomy and Physiology. Physiol Rev 83: 803–834, 2003; 10.1152/physrev.00002.2003.—A converging body of literature over the last 50 years has implicated the amygdala in assigning emotional significance or value to sensory information. In particular, the amygdala has been shown to be an essential component of the circuitry underlying fear-related responses. Disorders in the processing of fear-related information are likely to be the underlying cause of some anxiety disorders in humans such as posttraumatic stress. The amygdaloid complex is a group of more than 10 nuclei that are located in the midtemporal lobe. These nuclei can be distinguished both on cytoarchitectonic and connectional grounds. Anatomical tract tracing studies have shown that these nuclei have extensive intranuclear and internuclear connections. The afferent and efferent connections of the amygdala have also been mapped in detail, showing that the amygdaloid complex has extensive connections with cortical and subcortical regions. Analysis of fear conditioning in rats has suggested that long-term synaptic plasticity of inputs to the amygdala underlies the acquisition and perhaps storage of the fear memory. In agreement with this proposal, synaptic plasticity has been demonstrated at synapses in the amygdala in both in vitro and in vivo studies. In this review, we examine the anatomical and physiological substrates proposed to underlie amygdala function.

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Ionising Radiation Immediately Impairs Synaptic Plasticity-Associated Cytoskeletal Signalling Pathways in HT22 Cells and in Mouse Brain: An In Vitro/In Vivo Comparison Study

PLoS ONE ◽

10.1371/journal.pone.0110464 ◽

2014 ◽

Vol 9 (10) ◽

pp. e110464 ◽

Cited By ~ 28

Author(s):

Stefan J. Kempf ◽

Sonja Buratovic ◽

Christine von Toerne ◽

Simone Moertl ◽

Bo Stenerlöw ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mouse Brain ◽

Ionising Radiation ◽

Signalling Pathways ◽

Comparison Study ◽

Ht22 Cells

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DL-3-n-butylphthalide enhances synaptic plasticity in mouse model of brain impairments

STEMedicine ◽

10.37175/stemedicine.v3i1.113 ◽

2022 ◽

Vol 3 (1) ◽

pp. e113

Author(s):

Qian Ding ◽

Qian Yu ◽

Lei Tao ◽

Yifei Guo ◽

Juan Zhao ◽

...

Keyword(s):

Synaptic Plasticity ◽

Nmda Receptor ◽

Glutamate Release ◽

Field Potential ◽

Nmda Receptor Subunits ◽

Glutamate Level ◽

Regulatory Effects ◽

Glutaminase Activity

Synaptic impairment results in cognitive dysfunction of Alzheimer’s disease (AD). As a plant extract, it is found that DL-3-n-butylphthalide (L-NBP) rescues abnormal cognitive behaviors in AD animals. However, the regulatory effects of L-NBP on synaptic plasticity remains unclear. APP/PS1 mice at 12 months old received oral L-NBP treatment for 12 weeks. A water maze test assessed cognitive performances. In vitro patch-clamp recordings and in vivo field potential recordings were performed to evaluate synaptic plasticity. The protein expression of AMPA receptor subunits (GluR1 and GluR2) and NMDA receptor subunits (NR1, NR2A, and NR2B) was examined by Western blot. In addition, glutaminase activity and glutamate level in the hippocampus were measured by colorimetry to evaluate presynaptic glutamate release. L-NBP treatment could significantly improve learning and memory ability, upregulate NR2A and NR2B protein expressions, increase glutaminase activity and glutamate level in the hippocampus, and attenuate synaptic impairment transmission in the AD mice. L-NPB plays a beneficial role in AD mice by regulating NMDA receptor subunits’ expression and regulating presynaptic glutamate release.

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Cordycepin Improved Neuronal Synaptic Plasticity Through CREB-Induced NGF Up-Regulation Driven By Microglial M2 Polarization: A Symphony Communication Between Microglia and Neurons in AD

10.21203/rs.3.rs-184003/v1 ◽

2021 ◽

Author(s):

Linchi Jiao ◽

Mingyan Liu ◽

Xin Zhong ◽

Weifan Yao ◽

Guowei Ma ◽

...

Keyword(s):

Synaptic Plasticity ◽

Animal Behavior ◽

Cell Biology ◽

Neuronal Apoptosis ◽

Microglial Activation ◽

Neuroprotective Effect ◽

M2 Polarization ◽

Improved Learning

Abstract Background: The purpose of this study was to explore the molecular mechanism of the neuroprotective effect of Cordycepin (CCS) on improving the neuro-immune microenvironment of AD neurons by mediating microglial M2 polarization. Methods: We investigated microglial M2 polarization from M1, neuronal senescence, and synaptic plasticity by biological techniques such as animal behavior, cell biology, morphology, and bioinformatics. Results: CCS improved learning and memory impairment in 9-month-old APP/PS1 mice. CCS induced the microglial M2 polarization, up-regulated the expression and secretion level of NGF, and inhibited neuronal apoptosis, senescence, and synaptic damage caused by abnormal microglial activation in vivo and in vitro. CREB was activated by the M2 polarization and mediated the NGF expression and secretion after CCS treatment. CREB bound with the Sg3 promoter region of NGF (-1018~-1011), which increased NGF expression and secretion. CREB-induced NGF upregulation driven by microglial M2 polarization to improve the neuronal synaptic plasticity inhibits neuronal apoptosis and senescence. As a novel participant in the intercellular communication between MG and neurons, NGF contributed to the neuroprotective efficacy of CCS treatment. Conclusions: CCS improved the neuronal synaptic plasticity and senescence by promoting microglial M2 activation driven by CERB-induced NGF upregulation and conducted the symphony communication of MG-Neuron in AD.

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Tropomyosin isoforms in rat neurons: the different developmental profiles and distributions of TM-4 and TMBr-3 are consistent with different functions

Journal of Cell Science ◽

10.1242/jcs.107.10.2961 ◽

1994 ◽

Vol 107 (10) ◽

pp. 2961-2973 ◽

Cited By ~ 1

Author(s):

L. Had ◽

C. Faivre-Sarrailh ◽

C. Legrand ◽

J. Mery ◽

J. Brugidou ◽

...

Keyword(s):

Synaptic Plasticity ◽

Neurite Growth ◽

Growth Cones ◽

Actin Binding ◽

Cultured Neurons ◽

Immature Stages ◽

Tropomyosin Isoforms ◽

Developmental Profiles

Antipeptide antisera specific for TM-4 and TMBr-3, the two tropomyosin isoforms in neurons, were used to investigate the concentrations and distributions of these F-actin-binding proteins in neurons in vitro and in vivo. TM-4 and TMBr-3 tropomyosins had different developmental profiles. TM-4 was found mainly in immature stages, while the concentration of TMBr-3 increased with maturation. The two isoforms also had different subcellular distributions. TM-4 was concentrated in the growth cones of cultured neurons and, in vivo, in areas where neurites were growing. Later, when development was complete, TM-4 was restricted to postsynaptic sites in the cerebellar cortex, whereas TMBr-3 was found in the presynaptic terminals. These data suggest that the tropomyosin isoforms have different functions, through their interaction with the actin cytoskeleton. TM-4 may be involved in the motile events of neurite growth and synaptic plasticity, while TMBr-3 could play a role in stabilizing neuronal networks and synaptic functioning.

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ATP11B deficiency leads to impairment of hippocampal synaptic plasticity

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz042 ◽

2019 ◽

Vol 11 (8) ◽

pp. 688-702 ◽

Cited By ~ 3

Author(s):

Jiao Wang ◽

Weihao Li ◽

Fangfang Zhou ◽

Ruili Feng ◽

Fushuai Wang ◽

...

Keyword(s):

Signal Transduction ◽

Synaptic Plasticity ◽

Hippocampal Neurons ◽

Glutamate Release ◽

Dendritic Morphology ◽

Receptor Expression ◽

Hippocampal Synaptic Plasticity ◽

Synaptic Ultrastructure

Abstract Synaptic plasticity is known to regulate and support signal transduction between neurons, while synaptic dysfunction contributes to multiple neurological and other brain disorders; however, the specific mechanism underlying this process remains unclear. In the present study, abnormal neural and dendritic morphology was observed in the hippocampus following knockout of Atp11b both in vitro and in vivo. Moreover, ATP11B modified synaptic ultrastructure and promoted spine remodeling via the asymmetrical distribution of phosphatidylserine and enhancement of glutamate release, glutamate receptor expression, and intracellular Ca2+ concentration. Furthermore, experimental results also indicate that ATP11B regulated synaptic plasticity in hippocampal neurons through the MAPK14 signaling pathway. In conclusion, our data shed light on the possible mechanisms underlying the regulation of synaptic plasticity and lay the foundation for the exploration of proteins involved in signal transduction during this process.

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Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation

Neural Plasticity ◽

10.1155/2021/4090441 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Linhao Xu ◽

Yanli Bi ◽

Yizhou Xu ◽

Yihao Wu ◽

Xiaoxue Du ◽

...

Keyword(s):

Transcription Factor ◽

Synaptic Plasticity ◽

Signaling Pathway ◽

Intermittent Hypoxia ◽

Specific Chemical ◽

Activating Transcription Factor ◽

Induced Apoptosis

Our previous study showed that growth arrest- and DNA damage-inducible gene 153 (GAD153/CHOP) plays an important role in intermittent hypoxia- (IH-) induced apoptosis and impaired synaptic plasticity. This study is aimed at determining which signaling pathway is activated to induce CHOP and the role of this protein in mitochondria-dependent apoptosis induced by IH. In the in vivo study, mice were placed in IH chambers for 8 h daily over a period of 2 weeks; the IH chambers had oxygen (O2) concentrations that oscillated between 10% and 21%, cycling every 90 s. In the in vitro study, PC12 cells were exposed to 21% O2 (normoxia) or 8 IH cycles (25 min at 21% O2 and 35 min at 0.1% O2 for each cycle). After 2 weeks of IH treatment, we observed that the expression levels of phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF-4) and phosphorylated eukaryotic initiation factor 2 alpha (p-elf2α), were increased, but the levels of activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) were not increased. GSK2606414, a specific chemical inhibitor of the PERK pathway, reduced the expression of p-PERK, ATF-4, p-elf2α, and CHOP and rescued ER structure. In addition, Bax and Bak accumulated in the mitochondria after IH treatment, which induced cytochrome c release and initiated apoptosis. These effects were prevented by GSK2606414 and CHOP shRNA. Finally, the impaired long-term potentiation and long-term spatial memory in the IH group were rescued by GSK2606414. Together, the data from the in vitro and in vivo experiments indicate that IH-induced apoptosis and impaired synaptic plasticity were mediated by the PERK-ATF-4-CHOP pathway. Suppressing PERK-ATF-4-CHOP signaling pathway attenuated mitochondria-dependent apoptosis by reducing the expression of Bax and Bak in mitochondria, which may serve as novel adjunct therapeutic strategy for ameliorating obstructive sleep apnea- (OSA-) induced neurocognitive impairment.

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