scholarly journals A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis

2005 ◽  
Vol 168 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Emily Osterweil ◽  
David G. Wells ◽  
Mark S. Mooseker
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Dominant Negative ◽  
Myosin Vi ◽  
Receptor Endocytosis ◽  
Synapse Loss ◽  
Synaptic Structure ◽  
Acid Type ◽  
Significant Deficit ◽  
The Brain

Myosin VI (Myo6) is an actin-based motor protein implicated in clathrin-mediated endocytosis in nonneuronal cells, though little is known about its function in the nervous system. Here, we find that Myo6 is highly expressed throughout the brain, localized to synapses, and enriched at the postsynaptic density. Myo6-deficient (Snell's waltzer; sv/sv) hippocampus exhibits a decrease in synapse number, abnormally short dendritic spines, and profound astrogliosis. Similarly, cultured sv/sv hippocampal neurons display decreased numbers of synapses and dendritic spines, and dominant-negative disruption of Myo6 in wild-type hippocampal neurons induces synapse loss. Importantly, we find that sv/sv hippocampal neurons display a significant deficit in the stimulation-induced internalization of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid–type glutamate receptors (AMPARs), and that Myo6 exists in a complex with the AMPAR, AP-2, and SAP97 in brain. These results suggest that Myo6 plays a role in the clathrin-mediated endocytosis of AMPARs, and that its loss leads to alterations in synaptic structure and astrogliosis.

scholarly journals The brain-specific double-stranded RNA-binding protein Staufen2 is required for dendritic spine morphogenesis

2006 ◽  
Vol 172 (2) ◽  
pp. 221-231 ◽  
Author(s):  
Bernhard Goetze ◽  
Fabian Tuebing ◽  
Yunli Xie ◽  
Mario M. Dorostkar ◽  
Sabine Thomas ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Dominant Negative ◽  
Double Stranded Rna ◽  
Mature Neurons ◽  
Actin Mrna ◽  
The Brain

Mammalian Staufen2 (Stau2) is a member of the double-stranded RNA-binding protein family. Its expression is largely restricted to the brain. It is thought to play a role in the delivery of RNA to dendrites of polarized neurons. To investigate the function of Stau2 in mature neurons, we interfered with Stau2 expression by RNA interference (RNAi). Mature neurons lacking Stau2 displayed a significant reduction in the number of dendritic spines and an increase in filopodia-like structures. The number of PSD95-positive synapses and miniature excitatory postsynaptic currents were markedly reduced in Stau2 down-regulated neurons. Akin effects were caused by overexpression of dominant-negative Stau2. The observed phenotype could be rescued by overexpression of two RNAi cleavage-resistant Stau2 isoforms. In situ hybridization revealed reduced expression levels of β-actin mRNA and fewer dendritic β-actin mRNPs in Stau2 down-regulated neurons. Thus, our data suggest an important role for Stau2 in the formation and maintenance of dendritic spines of hippocampal neurons.

scholarly journals Cadherin activity is required for activity-induced spine remodeling

2004 ◽  
Vol 167 (5) ◽  
pp. 961-972 ◽  
Author(s):  
Ko Okamura ◽  
Hidekazu Tanaka ◽  
Yoshiki Yagita ◽  
Yoshinaga Saeki ◽  
Akihiko Taguchi ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Actin Polymerization ◽  
Fluorescent Protein ◽  
Cytochalasin D ◽  
Dominant Negative ◽  
Spine Head ◽  
Green Fluorescent ◽  
Activity Dependent

Neural activity induces the remodeling of pre- and postsynaptic membranes, which maintain their apposition through cell adhesion molecules. Among them, N-cadherin is redistributed, undergoes activity-dependent conformational changes, and is required for synaptic plasticity. Here, we show that depolarization induces the enlargement of the width of spine head, and that cadherin activity is essential for this synaptic rearrangement. Dendritic spines visualized with green fluorescent protein in hippocampal neurons showed an expansion by the activation of AMPA receptor, so that the synaptic apposition zone may be expanded. N-cadherin-venus fusion protein laterally dispersed along the expanding spine head. Overexpression of dominant-negative forms of N-cadherin resulted in the abrogation of the spine expansion. Inhibition of actin polymerization with cytochalasin D abolished the spine expansion. Together, our data suggest that cadherin-based adhesion machinery coupled with the actin-cytoskeleton is critical for the remodeling of synaptic apposition zone.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

scholarly journals Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

2016 ◽  
Vol 48 (7) ◽  
pp. 491-501 ◽  
Author(s):  
Madeliene Stump ◽  
Deng-Fu Guo ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
High Fat Diet ◽  
Control Diet ◽  
Cre Recombinase ◽  
Dominant Negative ◽  
High Fat ◽  
Pparγ Agonist ◽  
The Brain

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

Defective actin dynamics in dendritic spines: cause or consequence of age-induced cognitive decline?

2016 ◽  
Vol 397 (3) ◽  
pp. 223-229 ◽  
Author(s):  
Till Georg Alexander Mack ◽  
Patricia Kreis ◽  
Britta Johanna Eickholt
Keyword(s):  
Dendritic Spines ◽  
Neuronal Excitability ◽  
Replicative Senescence ◽  
Morphological Changes ◽  
Actin Dynamics ◽  
Cellular Processes ◽  
Filament Dynamics ◽  
Neuronal Soma ◽  
Deteriorating Process ◽  
The Brain

Abstract Ageing is a complex deteriorating process that coincides with changes in metabolism, replicative senescence, increased resistance to apoptosis, as well as progressive mitochondria dysfunction that lead to an increase production and accumulation of reactive oxygen species (ROS). Although controversy on the paradigm of the oxidative damage theory of ageing exists, persuasive studies in Caenorhabditis elegans and yeast have demonstrated that manipulation of ROS can modify the process of ageing and influences the damage of proteins, lipids and DNA. In neurons, ageing impacts on the intrinsic neuronal excitability, it decreases the size of neuronal soma and induces the loss of dendrites and dendritic spines. The actin cytoskeleton is an abundant and broadly expressed system that plays critical functions in many cellular processes ranging from cell motility to controlling cell shape and polarity. It is thus hardly surprising that the expression and the function of actin in neurons is crucial for the morphological changes that occur in the brain throughout life. We propose that alterations in actin filament dynamics in dendritic spines may be one of the key events contributing to the initial phases of ageing in the brain.

scholarly journals Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity

2017 ◽  
Vol 216 (10) ◽  
pp. 3161-3178 ◽  
Author(s):  
Xiaoyi Qu ◽  
Feng Ning Yuan ◽  
Carlo Corona ◽  
Silvia Pasini ◽  
Maria Elena Pero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Axonal Transport ◽  
Dendritic Spines ◽  
Posttranslational Modifications ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Driving Factors ◽  
Hyperphosphorylated Tau ◽  
Tau Hyperphosphorylation

Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

scholarly journals Post-status epilepticus treatment with the Fyn inhibitor, saracatinib, improves cognitive function in mice

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xin-Ming Luo ◽  
Jing Zhao ◽  
Wen-Yue Wu ◽  
Jie Fu ◽  
Zheng-Yu Li ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Cognitive Function ◽  
Cognitive Deficits ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Water Maze ◽  
Behavioral Tests ◽  
Life Threatening ◽  
The Brain ◽  
Normal Object

Abstract Background Status epilepticus (SE) is a life-threatening neurological disorder. The hippocampus, as an important area of the brain that regulates cognitive function, is usually damaged after SE, and cognitive deficits often result from hippocampal neurons lost after SE. Fyn, a non-receptor Src family of tyrosine kinases, is potentially associated with the onset of seizure. Saracatinib, a Fyn inhibitor, suppresses epileptogenesis and reduces epileptiform spikes. However, whether saracatinib inhibits cognitive deficits after SE is still unknown. Methods In the present study, a pilocarpine-induced SE mouse model was used to answer this question by using the Morris water maze and normal object recognition behavioral tests. Results We found that saracatinib inhibited the loss in cognitive function following SE. Furthermore, we found that the number of hippocampal neurons in the saracatinib treatment group was increased, when compared to the SE group. Conclusions These results showed that saracatinib can improve cognitive functions by reducing the loss of hippocampal neurons after SE, suggesting that Fyn dysfunction is involved in cognitive deficits after SE, and that the inhibition of Fyn is a possible treatment to improve cognitive function in SE patients.

scholarly journals REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Percy Griffin ◽  
Patrick W Sheehan ◽  
Julie M Dimitry ◽  
Chun Guo ◽  
Michael F Kanan ◽  
...  
Keyword(s):  
Daily Variation ◽  
Brain Health ◽  
Astrocyte Activation ◽  
Synaptic Regulation ◽  
Microglial Phagocytosis ◽  
Synapse Loss ◽  
The Brain ◽  
Master Clock ◽  
Clock Protein ◽  
Diurnal Regulation

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

scholarly journals Latent learning drives sleep-dependent plasticity in distinct CA1 subpopulations

2020 ◽  
Author(s):  
Wei Guo ◽  
Jie J. Zhang ◽  
Jonathan P. Newman ◽  
Matthew A. Wilson
Keyword(s):  
Hippocampal Neurons ◽  
Dimensional Manifold ◽  
Latent Learning ◽  
Neural Ensembles ◽  
Correlated Activity ◽  
Place Fields ◽  
Internal States ◽  
Low Dimensional ◽  
Low Dimensional Manifold ◽  
The Brain

AbstractLatent learning allows the brain the transform experiences into cognitive maps, a form of implicit memory, without reinforced training. Its mechanism is unclear. We tracked the internal states of the hippocampal neural ensembles and discovered that during latent learning of a spatial map, the state space evolved into a low-dimensional manifold that topologically resembled the physical environment. This process requires repeated experiences and sleep in-between. Further investigations revealed that a subset of hippocampal neurons, instead of rapidly forming place fields in a novel environment, remained weakly tuned but gradually developed correlated activity with other neurons. These ‘weakly spatial’ neurons bond activity of neurons with stronger spatial tuning, linking discrete place fields into a map that supports flexible navigation.

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