scholarly journals Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders

2018 ◽  
Author(s):  
Filippo Erli ◽  
Alish B. Palmos ◽  
Pooja Raval ◽  
Jayanta Mukherjee ◽  
Katherine J. Sellers ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Cortical Neurons ◽  
Neuropsychiatric Disorders ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Cellular Model ◽  
Spine Density ◽  
Beneficial Effects ◽  
17Β Estradiol ◽  
Spine Number

AbstractLoss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number.

scholarly journals BDNF signaling during the lifetime of dendritic spines

2020 ◽  
Vol 382 (1) ◽  
pp. 185-199 ◽  
Author(s):  
Marta Zagrebelsky ◽  
Charlotte Tacke ◽  
Martin Korte
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Neurological Disorders ◽  
Current Knowledge ◽  
Conclusive Evidence ◽  
Excitatory Synapses ◽  
Neuronal Homeostasis ◽  
Bdnf Signaling ◽  
Spine Number

Abstract Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

scholarly journals Letrozole Potentiates Mitochondrial and Dendritic Spine Impairments Induced byβAmyloid

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
P. K.-Y. Chang ◽  
S. Boridy ◽  
R. A. McKinney ◽  
D. Maysinger
Keyword(s):  
Aromatase Inhibitor ◽  
Dendritic Spine ◽  
Cognitive Abilities ◽  
Mitochondrial Morphology ◽  
Spine Density ◽  
Postsynaptic Protein ◽  
Letrozole Treatment ◽  
Mitochondrial Volume ◽  
Synaptic Structures ◽  
Spine Number

Reduced estrogens, either through aging or postsurgery breast cancer treatment with the oral nonsteroidal aromatase inhibitor letrozole, are linked with declined cognitive abilities. However, a direct link between letrozole and neuronal deficits induced by pathogenic insults associated with aging such as beta amyloid (Aβ1–42) has not been established. The objective of this study was to determine if letrozole aggravates synaptic deficits concurrent withAβ1–42insult. We examined the effects of letrozole and oligomericAβ1–42treatment in dissociated and organotypic hippocampal slice cultures. Changes in glial cell morphology, neuronal mitochondria, and synaptic structures upon letrozole treatment were monitored by confocal microscopy, as they were shown to be affected byAβ1–42oligomers. OligomericAβ1–42or letrozole alone caused decreases in mitochondrial volume, dendritic spine density, synaptophysin (synaptic marker), and the postsynaptic protein, synaptopodin. Here, we demonstrated that mitochondrial and synaptic structural deficits were exacerbated when letrozole therapy was combined withAβ1–42treatment. Our novel findings suggest that letrozole may increase neuronal susceptibility to pathological insults, such as oligomericAβ1–42in Alzheimer’s disease (AD). These changes in dendritic spine number, synaptic protein expression, and mitochondrial morphology may, in part, explain the increased prevalence of cognitive decline associated with aromatase inhibitor use.

scholarly journals Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine dysgenesis

2020 ◽  
Author(s):  
Masashi Ueda ◽  
Tohru Matsuki ◽  
Masahide Fukada ◽  
Shima Eda ◽  
Akie Toya ◽  
...  
Keyword(s):  
Neural Development ◽  
Dendritic Spine ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Rna Splicing ◽  
De Novo ◽  
Facial Dysmorphism ◽  
Spine Density ◽  
Musculoskeletal Abnormalities ◽  
Human Wild Type

Abstract Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a rare congenital anomaly syndrome characterized by intellectual disability, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and some visceral malformations is caused by de novo heterozygous mutations of the SON gene. The nuclear protein SON is involved in gene transcription and RNA splicing; however, the roles of SON in neural development remain undetermined. We investigated the effects of Son knockdown on neural development in mice and found that Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons. The induction of human wild-type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. We also applied truncated SON proteins encoded by disease-associated mutant SON genes for rescue experiments and found that a truncated SON protein encoded by the most prevalent SON mutant found in ZTTK syndrome rescued the neural abnormalities while another much shorter mutant SON protein did not. These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine dysgenesis, which seem neuropathological bases of the neural symptoms of ZTTK syndrome. In addition, the results strongly suggest that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.

scholarly journals Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Pu-Yun Shih ◽  
Bing-Yuan Hsieh ◽  
Ching-Yen Tsai ◽  
Chiu-An Lo ◽  
Brian E. Chen ◽  
...  
Keyword(s):  
Social Interaction ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Short Form ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Spine Density ◽  
Spine Formation ◽  
Molecular Features

Abstract Abnormal synaptic formation and signaling is one of the key molecular features of autism spectrum disorders (ASD). Cortactin binding protein 2 (CTTNBP2), an ASD-linked gene, is known to regulate the subcellular distribution of synaptic proteins, such as cortactin, thereby controlling dendritic spine formation and maintenance. However, it remains unclear how ASD-linked mutations of CTTNBP2 influence its function. Here, using cultured hippocampal neurons and knockin mouse models, we screen seven ASD-linked mutations in the short form of the Cttnbp2 gene and identify that M120I, R533* and D570Y mutations impair CTTNBP2 protein–protein interactions via divergent mechanisms to reduce dendritic spine density in neurons. R533* mutation impairs CTTNBP2 interaction with cortactin due to lack of the C-terminal proline-rich domain. Through an N–C terminal interaction, M120I mutation at the N-terminal region of CTTNBP2 also negatively influences cortactin interaction. D570Y mutation increases the association of CTTNBP2 with microtubule, resulting in a dendritic localization of CTTNBP2, consequently reducing the distribution of CTTNBP2 in dendritic spines and impairing the synaptic function of CTTNBP2. Finally, we generated heterozygous M120I knockin mice to mimic the genetic variation of patients and found they exhibit reduced social interaction. Our study elucidates that different ASD-linked mutations of CTTNBP2 result in diverse molecular deficits, but all have the similar consequence of synaptic impairment.

scholarly journals Pannexin 1 regulates spiny protrusion dynamics in cortical neurons

2020 ◽  
Author(s):  
Juan C. Sanchez-Arias ◽  
Rebecca C. Candlish ◽  
Leigh Anne Swayne
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Cortical Neurons ◽  
Neuronal Networks ◽  
Local Environment ◽  
Spine Density ◽  
Pannexin 1 ◽  
Developing Neurons ◽  
The Impact

AbstractThe integration of neurons into networks relies on the formation of dendritic spines. These specialized structures arise from dynamic filopodia-like spiny protrusions. Recently, it was discovered that cortical neurons lacking the channel protein Pannexin 1 (Panx1) exhibited larger and more complicated neuronal networks, as well as, higher dendritic spine densities. Here, we expanded on those findings to investigate whether the increase in dendritic spine density associated with lack of Panx1 was due to differences in the rates of spine dynamics. Using a fluorescent membrane tag (mCherry-CD9-10) to visualize spiny protrusions in developing neurons (at 10 days-in-vitro, DIV10) we confirmed that lack of Panx1 leads to higher spiny protrusion density while transient transfection of Panx1 leads to decreased spiny protrusion density. To quantify the impact of Panx1 expression on spiny protrusion formation, elimination, and motility, we used live cell imaging in DIV10 neurons (1 frame every 5 seconds for 10 minutes). We discovered, that at DIV10, lack of Panx1 KO stabilized spiny protrusions. Notably, re-expression of Panx1 in Panx1 knockout neurons resulted in a significant increase in spiny protrusion motility and turnover. In summary, these new data revealed that Panx1 regulates the development of dendritic spines by controlling protrusion dynamics.Significance statementCells in the brain form intricate and specialized networks - neuronal networks - in charge of processing sensations, executing movement commands, and storing memories. To do this, brain cells extend microscopic protrusions - spiny protrusions - which are highly dynamic and survey the local environment to contact other cells. Those contact sites are known as synapses and undergo further stabilization and maturation establishing the function and efficiency of neuronal networks. Our work shows that removal of Panx1 increases the stability and decreases the turnover of spiny protrusion on young neurons.

scholarly journals Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1655
Author(s):  
Kyung-Min Han ◽  
Ri Jin Kang ◽  
Hyongjun Jeon ◽  
Hyun-ju Lee ◽  
Ji-Soo Lee ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dendritic Spine ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Regulatory Function ◽  
Spine Density ◽  
App Processing ◽  
Beneficial Effects

The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer’s disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology in vitro and in vivo. Regorafenib affected AKT signaling to attenuate lipopolysaccharide (LPS)-mediated expression of proinflammatory cytokines in BV2 microglial cells and primary cultured microglia and astrocytes. In addition, regorafenib suppressed LPS-induced neuroinflammatory responses in LPS-injected wild-type mice. In 5x FAD mice (a mouse model of AD), regorafenib ameliorated AD pathology, as evidenced by increased dendritic spine density and decreased Aβ plaque levels, by modulating APP processing and APP processing-associated proteins. Furthermore, regorafenib-injected 5x FAD mice displayed significantly reduced tau phosphorylation at T212 and S214 (AT100) due to the downregulation of glycogen synthase kinase-3 beta (GSK3β) activity. Taken together, our results indicate that regorafenib has beneficial effects on neuroinflammation, AD pathology, and dendritic spine formation in vitro and in vivo.

Attenuation of dendritic spine density in the perirhinal cortex following 17β-Estradiol replacement in the rat

Hippocampus ◽  
2015 ◽  
Vol 25 (11) ◽  
pp. 1212-1216 ◽  
Author(s):  
Nicole J. Gervais ◽  
Dave G. Mumby ◽  
Wayne G. Brake
Keyword(s):  
Dendritic Spine ◽  
Perirhinal Cortex ◽  
Spine Density ◽  
Dendritic Spine Density ◽  
17Β Estradiol
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