Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids

2019 ◽  
Vol 30 (4) ◽  
pp. 2627-2641 ◽  
Author(s):  
Nicola Brandt ◽  
Ricardo Vierk ◽  
Lars Fester ◽  
Max Anstötz ◽  
Lepu Zhou ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Sex Chromosome ◽  
Chromosome Complement ◽  
Hippocampal Synaptic Plasticity ◽  
And Function ◽  
Mushroom Spines ◽  
The Brain

Abstract Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.

scholarly journals ATP11B deficiency leads to impairment of hippocampal synaptic plasticity

2019 ◽  
Vol 11 (8) ◽  
pp. 688-702 ◽  
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.

scholarly journals DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

2019 ◽  
Vol 116 (50) ◽  
pp. 25322-25328 ◽  
Author(s):  
Yi Liu ◽  
Xiaopin Ma ◽  
Hisashi Fujioka ◽  
Jun Liu ◽  
Shengdi Chen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cellular Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Efflux ◽  
And Function ◽  
The Brain ◽  
Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

FKBP51 Modulates Hippocampal Size and Function in Post-translational Regulation of Parkin

2021 ◽  
Author(s):  
Bin Qiu ◽  
Zhaohui Zhong ◽  
Shawn Righter ◽  
Yuxue Xu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Translational Regulation ◽  
Disease Onset ◽  
Fold Increase ◽  
Knock Out ◽  
Fk506 Binding Protein ◽  
Protein Levels ◽  
And Function

Abstract FK506-binding protein 51 (encoded by Fkpb51) has been associated with stress-related mental illness. To identify its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assist morphological analysis identified that Fkbp51 knock-out (KO) mice possess more elongated CA and DG but shorter in height in coronal section when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls, pharmacological manipulation experiments suggest that this may occur through regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support that FKBP51 regulates microtubule-associated protein expression. Furthermore, in the absence of differences in mRNA expression, Fkbp51 KO hippocampus exhibited decreases in βIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory of Parkin by FKBP51 and significance of their interaction on disease onset.

STEM-18. STROMAL EXTRACELLULAR VESICLES DRIVE GLIOMA STEM CELL REPROGRAMMING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi24-vi25
Author(s):  
Lata Adnani ◽  
Brian Meehan ◽  
Jordan Kassouf ◽  
Cristiana Spinelli ◽  
Nadim Tawil ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Extracellular Vesicle ◽  
Host Cells ◽  
Tumour Mass ◽  
Membrane Structures ◽  
And Function ◽  
Rate Limiting ◽  
The Brain

Abstract Glioblastoma multiforme (GBM) represents the most frequent and lethal form of brain tumors originating from glioma stem cells (GSCs). GBM remains lethal because the rate limiting patho-mechanisms remain poorly understood. In this regard, few limitations involve the diversity 'between' cellular states and the molecular/cellular complexity 'within' the tumour mass. Using cell based- and mouse- models, we explored extracellular vesicle (EV) mediated interactions between cancer and stromal cells impacting phenotypes of GSCs as a function of their molecular subtype. EVs are spherical membrane structures that cells release to expel different molecular cargo (lipids, proteins, RNA, DNA), which can be transported across a distance in the brain and taken up by various ‘recipient’ cells resulting in reprogramming of the recipient cell's content and function. In vivo, GSCs altered their pattern of NOTCH signalling and molecular phenotype as a function of proximity to non-transformed host cells in the brain. In vitro stromal EVs altered GSC sphere forming capacity, proteome and expression of mesenchymal markers. Thus, EV mediated tumour-stromal interactions could represent a biological switch and a novel targeting point in the biology of GBM.

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

2010 ◽  
Vol 108 (1) ◽  
pp. 379-384 ◽  
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.

scholarly journals Fragile X syndrome patient-derived neurons developing in the mouse brain show FMR1 -dependent phenotypes

2021 ◽  
Author(s):  
Marine A Krzisch ◽  
Hao A Wu ◽  
Bingbing Yuan ◽  
Troy W. Whitfield ◽  
X. Shawn Liu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Neuronal Development ◽  
Fragile X ◽  
In Vitro Models ◽  
Synaptic Activity ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
And Function ◽  
The Brain

Abnormal neuronal development in Fragile X syndrome (FXS) is poorly understood. Data on FXS patients remain scarce and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. Here, we co-injected neural precursor cells (NPCs) from FXS patient-derived and corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Single-cell RNA sequencing of transplanted cells revealed upregulated excitatory synaptic transmission and neuronal differentiation pathways in FXS neurons. Immunofluorescence analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, increased percentages of Arc- and Egr1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons pointed to an increase in synaptic activity and synaptic strength as compared to control. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3D context, and could be used to test new therapeutic compounds correcting neuronal development defects in FXS.

scholarly journals MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival

2007 ◽  
Vol 204 (9) ◽  
pp. 2063-2074 ◽  
Author(s):  
Younghwa Kim ◽  
Ping Zhou ◽  
Liping Qian ◽  
Jen-Zen Chuang ◽  
Jessica Lee ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Artificial Chromosome ◽  
Adaptor Proteins ◽  
Innate Immune ◽  
Molecular Structures ◽  
Endogenous Expression ◽  
Microbial Products ◽  
The Brain ◽  
Deficient Mice

The innate immune system relies on evolutionally conserved Toll-like receptors (TLRs) to recognize diverse microbial molecular structures. Most TLRs depend on a family of adaptor proteins termed MyD88s to transduce their signals. Critical roles of MyD88-1–4 in host defense were demonstrated by defective immune responses in knockout mice. In contrast, the sites of expression and functions of vertebrate MyD88-5 have remained elusive. We show that MyD88-5 is distinct from other MyD88s in that MyD88-5 is preferentially expressed in neurons, colocalizes in part with mitochondria and JNK3, and regulates neuronal death. We prepared MyD88-5/GFP transgenic mice via a bacterial artificial chromosome to preserve its endogenous expression pattern. MyD88-5/GFP was detected chiefly in the brain, where it associated with punctate structures within neurons and copurified in part with mitochondria. In vitro, MyD88-5 coimmunoprecipitated with JNK3 and recruited JNK3 from cytosol to mitochondria. Hippocampal neurons from MyD88-5–deficient mice were protected from death after deprivation of oxygen and glucose. In contrast, MyD88-5–null macrophages behaved like wild-type cells in their response to microbial products. Thus, MyD88-5 appears unique among MyD88s in functioning to mediate stress-induced neuronal toxicity.

scholarly journals Decreased neuronal excitability in hippocampal neurons of mice exposed to cyclic hypoxia

2001 ◽  
Vol 91 (3) ◽  
pp. 1245-1250 ◽  
Author(s):  
Xiang Q. Gu ◽  
Gabriel G. Haddad
Keyword(s):  
Membrane Potential ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Ca1 Neurons ◽  
Recovery From Inactivation ◽  
Channel Expression ◽  
Steady State Inactivation ◽  
And Function

To study the physiological effects of chronic intermittent hypoxia on neuronal excitability and function in mice, we exposed animals to cyclic hypoxia for 8 h daily (12 cycles/h) for ∼4 wk, starting at 2–3 days of age, and examined the properties of freshly dissociated hippocampal neurons in vitro. Compared with control (Con) hippocampal CA1 neurons, exposed (Cyc) neurons showed action potentials (AP) with a smaller amplitude and a longer duration and a more depolarized resting membrane potential. They also have a lower rate of spontaneous firing of AP and a higher rheobase. Furthermore, there was downregulation of the Na+ current density in Cyc compared with Con neurons (356.09 ± 54.03 pA/pF in Cyc neurons vs. 508.48 ± 67.30 pA/pF in Con, P < 0.04). Na+ channel characteristics, including activation, steady-state inactivation, and recovery from inactivation, were similar in both groups. The deactivation rate, however, was much larger in Cyc than in Con (at −100 mV, time constant for deactivation = 0.37 ± 0.04 ms in Cyc neurons and 0.18 ± 0.01 ms in Con neurons). We conclude that the decreased neuronal excitability in mice neurons treated with cyclic hypoxia is due, at least in part, to differences in passive properties (e.g., resting membrane potential) and in Na+ channel expression and/or regulation. We hypothesize that this decreased excitability is an adaptive response that attempts to decrease the energy expenditure that is used for adjusting disturbances in ionic homeostasis in low-O2conditions.

scholarly journals THE EFFECT OF DEPRIVATION OF GLUCOSE ON THE ULTRASTRUCTURE AND FUNCTION OF THE SUPERIOR CERVICAL GANGLION OF THE RAT IN VITRO

1966 ◽  
Vol 29 (2) ◽  
pp. 267-285 ◽  
Author(s):  
P. Nicolescu ◽  
M. Dolivo ◽  
C. Rouiller ◽  
C. Foroglou-Kerameus
Keyword(s):  
Synaptic Transmission ◽  
Ganglion Cells ◽  
Glucose Deprivation ◽  
Axonal Conduction ◽  
Electrophysiological Measurements ◽  
Cervical Ganglion ◽  
Cervical Sympathetic ◽  
Ultrastructure And Function ◽  
And Function

The superior cervical sympathetic ganglion of the rat kept in vitro in a bicarbonate-buffered Krebs' solution retains its capacity for synaptic transmission and axonal conduction during more than 36 hr. After glucose withdrawal, synaptic transmission is lost in 2½ hr and this loss is irreversible; on the other hand, axonal conduction can still be measured on the postganglionic nerve for more than 24 hr after glucose deprivation. Electrophysiological measurements as well as electron microscope studies revealed specific changes at the level of the presynaptic terminal processes, while the ganglion cells and the satellite cells remained relatively unaltered. The presynaptic lesion due to lack of glucose can be prevented by keeping the preparation in vitro at 6°C. This strongly suggests that this lesion results from a major disturbance of the metabolism of the presynaptic fibers.

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