scholarly journals Autism-Associated Chromatin Regulator Brg1/SmarcA4 is Required for Synapse Development and MEF2-mediated Synapse Remodeling

2015 ◽  
pp. MCB.00534-15 ◽  
Author(s):  
Zilai Zhang ◽  
Mou Cao ◽  
Chia-Wei Chang ◽  
Cindy Wang ◽  
Xuanming Shi ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Large Scale ◽  
Target Genes ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
Synapse Development ◽  
Spine Density ◽  
Synapse Elimination ◽  
Specific Subset

Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predictedBrg1/SmarcA4as one of the key nodes of the ASD gene network. We report thatBrg1deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronalBrg1deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD-associated transcription factor MEF2 and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles both in synapse development/maturation and in MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD.

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 TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
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.

scholarly journals The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

2020 ◽  
Author(s):  
Stephanie K. Jones ◽  
Jennifer Rha ◽  
Sarah Kim ◽  
Kevin J. Morris ◽  
Omotola F. Omotade ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Spine Density ◽  
Dendritic Spine Density

AbstractZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), an evolutionarily conserved member of a class of tandem zinc finger (CCCH) polyadenosine (polyA) RNA binding proteins, is associated with a form of heritable, nonsyndromic autosomal recessive intellectual disability. Previous studies of a loss of function mouse model, Zc3h14Δex13/Δex13, provide evidence that ZC3H14 is essential for proper brain function, specifically for working memory. To expand on these findings, we analyzed the dendrites and dendritic spines of hippocampal neurons from Zc3h14Δex13/Δex13 mice, both in situ and in vitro. These studies reveal that loss of ZC3H14 is associated with a decrease in total spine density in hippocampal neurons in vitro as well as in the dentate gyrus of 5-month old mice analyzed in situ. This reduction in spine density in vitro results from a decrease in the number of mushroom-shaped spines, which is rescued by exogenous expression of ZC3H14. We next performed biochemical analyses of synaptosomes prepared from whole wild-type and Zc3h14Δex13/Δex13 mouse brains to determine if there are changes in steady state levels of postsynaptic proteins upon loss of ZC3H14. We found that ZC3H14 is present within synaptosomes and that a crucial postsynaptic protein, CaMKIIα, is significantly increased in these synaptosomal fractions upon loss of ZC3H14. Together, these results demonstrate that ZC3H14 is necessary for proper dendritic spine density in cultured hippocampal neurons and in some regions of the mouse brain. These findings provide insight into how a ubiquitously expressed RNA binding protein leads to neuronal-specific defects that result in brain dysfunction.

scholarly journals Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

2020 ◽  
Vol 21 (9) ◽  
pp. 3079 ◽  
Author(s):  
Abhisarika Patnaik ◽  
Eleonora Spiombi ◽  
Angelisa Frasca ◽  
Nicoletta Landsberger ◽  
Marta Zagrebelsky ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Rett Syndrome ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Neurological Diseases ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Spine Density ◽  
Neuronal Structure ◽  
Cellular Mechanisms

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

Rapid Effects of Estradiol on Dendritic Spines and Synaptic Plasticity in the Male and Female Hippocampus

2020 ◽  
pp. 38-47
Author(s):  
Asami Kato ◽  
Gen Murakami ◽  
Yasushi Hojo ◽  
Sigeo Horie ◽  
Suguru Kawato
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Spine Density ◽  
Male And Female ◽  
Dendritic Spine Density ◽  
Male And Female Rats ◽  
Rapid Modulation

Although the potent estrogen, 17β‎-estradiol (E2), has long been known to regulate the hippocampal dendritic spine density and synaptic plasticity, the molecular mechanisms through which it does so are less well understood. This chapter discusses the rapid modulation of hippocampal dendritic spine density and synaptic plasticity in male and female rats, with particular attention to studies in hippocampal slices from male rats. Among the mechanisms described are the roles of specific cell-signaling kinases and estrogen receptors in mediating the effects of E2 and progesterone on hippocampal neurons. In addition, dynamic changes of spine structures over time and sex differences in spine regulation are also considered. Finally, the chapter ends by discussing the importance of local hippocampal synthesis of E2 and androgens to hippocampal spine morphology and plasticity.

scholarly journals Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation

2013 ◽  
Vol 24 (10) ◽  
pp. 1602-1613 ◽  
Author(s):  
Shuhei Ueda ◽  
Manabu Negishi ◽  
Hironori Katoh
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Actin Binding ◽  
Spine Density ◽  
Nucleotide Exchange ◽  
Spine Formation ◽  
Nucleotide Exchange Factor ◽  
Important Interaction

In neuronal development, dendritic spine formation is important for the establishment of excitatory synaptic connectivity and functional neural circuits. Developmental deficiency in spine formation results in multiple neuropsychiatric disorders. Dock4, a guanine nucleotide exchange factor (GEF) for Rac, has been reported as a candidate genetic risk factor for autism, dyslexia, and schizophrenia. We previously showed that Dock4 is expressed in hippocampal neurons. However, the functions of Dock4 in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show that Dock4 is highly concentrated in dendritic spines and implicated in spine formation via interaction with the actin-binding protein cortactin. In cultured neurons, short hairpin RNA (shRNA)–mediated knockdown of Dock4 reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-type Dock4 but not by a GEF-deficient mutant of Dock4 or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppresses Dock4-mediated spine formation. Taken together, the results show a novel and functionally important interaction between Dock4 and cortactin for regulating dendritic spine formation via activation of Rac.

scholarly journals Cirbp-PSD95 axis protects against hypobaric hypoxia-induced aberrant morphology of hippocampal dendritic spines and cognitive deficits

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yang Zhou ◽  
Huanyu Lu ◽  
Ying Liu ◽  
Zaihua Zhao ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Hypobaric Hypoxia ◽  
Rna Binding ◽  
Spine Injury ◽  
Spine Density ◽  
Hypoxia Exposure ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region

AbstractHypobaric hypoxia (HH) is a typical characteristic of high altitude environment and causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction and cognitive retardation. Here, we sought to understand the mechanisms underlying cognitive deficits under HH exposure. Our results showed that hypobaric hypoxia exposure impaired cognitive function and suppressed dendritic spine density accompanied with increased neck length in both basal and apical hippocampal CA1 region neurons in mice. The expression of PSD95, a vital synaptic scaffolding molecule, is down-regulated by hypobaric hypoxia exposure and post-transcriptionally regulated by cold-inducible RNA-binding protein (Cirbp) through 3′-UTR region binding. PSD95 expressing alleviates hypoxia-induced dendritic spine morphology changes of hippocampal neurons and memory deterioration. Moreover, overexpressed Cirbp in hippocampus rescues HH-induced abnormal expression of PSD95 and attenuates hypoxia-induced dendritic spine injury and cognitive retardation. Thus, our findings reveal a novel mechanism that Cirbp-PSD-95 axis appears to play an essential role in HH-induced cognitive dysfunction in mice.

scholarly journals Age- and Sex-Specific Fear Conditioning Deficits in Mice Lacking Pcdh10, an Autism Associated Gene

2020 ◽  
Author(s):  
Sarah L. Ferri ◽  
Holly C. Dow ◽  
Hannah Schoch ◽  
Ji Youn Lee ◽  
Edward S. Brodkin ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Dendritic Spine ◽  
Basolateral Amygdala ◽  
Partial Agonist ◽  
Autism Spectrum ◽  
Contextual Fear Conditioning ◽  
Dark Phase ◽  
Spine Density ◽  
Social And Emotional ◽  
Male Specific

AbstractPCDH10 is a gene associated with Autism Spectrum Disorder. It is involved in the growth of thalamocortical projections and dendritic spine elimination. Previously, we characterized mice Pcdh10 haploinsufficient mice (Pcdh10+/− mice) and found male-specific social deficits that are rescued by N-methyl-D-aspartate receptor (NMDAR) partial agonist d-cycloserine, increased ultrasonic vocalizations in pups, and dark phase hypoactivity. In addition, we determined that the basolateral amygdala (BLA) of these mice exhibited increased dendritic spine density of immature morphology, decreased NMDAR expression, and decreased gamma synchronization. Here, we further characterize Pcdh10+/− mice by testing for fear memory, which relies upon BLA function. We used both male and female Pcdh10+/− mice and their wild-type littermates at two ages, juvenile and adult, and in two learning paradigms, cued and contextual fear conditioning. We found that males at both ages and in both assays exhibited fear conditioning deficits, but females were only impaired as adults in the cued condition. These data are further evidence for male-specific alterations in BLA-related behaviors in Pcdh10+/− mice, and suggest that these mice may be a useful model for dissecting male specific brain and behavioral phenotypes relevant to social and emotional behaviors.

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