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Author: Deepak P Srivastava (38)


Oct
2017

Estrogen plays a critical role in many physiological processes and exerts profound effects on behavior by regulating neuronal excitability. While estrogen has been established to exert effects on dendritic morphology and excitatory neurotransmission its role in regulating neuronal inhibition is poorly understood. Fast synaptic inhibition in the adult brain is mediated by specialized populations of γ-c areceptors (GABARs) that are selectively enriched at synapses, a process dependent upon their interaction with the inhibitory scaffold protein gephyrin.

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Oct
2017

Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death.

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Feb
2018

Steroids have an important role in growth, development, sexual differentiation and reproduction. All four classes of steroids, androgens, oestrogens, progestogens and glucocorticoids, have varying effects on the brain. Androgens and oestrogens are involved in the sexual differentiation of the brain, and also influence cognition.

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Feb
2018

Progestins bind to the progestin receptor (PR) isoforms, PR-A and PR-B, in brain to influence development, female reproduction, anxiety, and stress. Hormone-activated PRs associate with multiple proteins to form functional complexes. In the present study, proteins from female mouse hypothalamus that associate with PR were isolated using affinity pull-down assays with glutathione S-transferase-tagged mouse PR-A and PR-B.

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Dec
2017

The fundamental role of the brain-specific myelin transcription factor 1-like (MYT1L) gene in cases of intellectual disability and in the etiology of neurodevelopmental disorders is increasingly recognized. Yet, its function remains under-investigated. Here, we identify a network of helix-loop-helix (HLH) transcriptional regulators controlled by MYT1L, as indicated by our analyses in human neural stem cells and in the human brain.

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Jul
2017

Variation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia and bipolar disorder. Evidence suggests that ZNF804A is a regulator of gene transcription and is present in nuclear and extranuclear compartments. However, a detailed examination of ZNF804A distribution and its neuronal functions has yet to be performed.

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Dec
1969

Chromosome 10q24.32-q24.33 is one of the most robustly supported risk loci to emerge from genome-wide association studies (GWAS) of schizophrenia.

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Dec
1969

Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity, and behaviour. Abnormal development or regulation of excitatory synapses has also been strongly implicated in many neurodevelopmental, psychiatric, and neurodegenerative disorders. In the mammalian forebrain, the majority of excitatory synapses are located on dendritic spines, specialized dendritic protrusions that are enriched in actin.

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Aug
2015

Conditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native neural cells to investigate physiological mechanisms in both health and disease. However, in order to recognise the utility of such cells, it is critical to determine whether they retain characteristics of their tissue of origin and generate appropriate neural cell types upon differentiation. To this end, we have characterised the conditionally immortalised, cortically-derived, human NPC line, CTX0E16, investigating the molecular and cellular phenotype of differentiated neurons to determine whether they possess characteristics of cortical glutamatergic neurons.

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Aug
2015

This article is part of a Special Issue "Estradiol and Cognition". Over recent years tremendous progress has been made towards understanding the molecular and cellular mechanism by which estrogens exert enhancing effects on cognition, and how they act as a neuroprotective or neurotrophic agent in disease. Currently, much of this work has been carried out in animal models with only a limited number of studies using native human tissue or cells.

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Dec
1969

In the mammalian forebrain, the majority of excitatory synapses occur on dendritic spines. Changes in the number of these structures is important for brain development, plasticity and the refinement of neuronal circuits. The formation of excitatory synapses involves the coordinated formation of dendritic spines and targeting of multi-protein complexes to nascent connections.

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Dec
2014

Pyramidal neurons in the mammalian forebrain receive their synaptic inputs through their dendritic trees, and dendritic spines are the sites of most excitatory synapses. Dendritic spine structure is important for brain development and plasticity. Kalirin-7 is a guanine nucleotide-exchange factor for the small GTPase Rac1 and is a critical regulator of dendritic spine remodeling.

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Jan
2015

There is now a growing appreciation that estrogens are capable of rapidly activating a number of signaling cascades within the central nervous system. In addition, there are an increasing number of studies reporting that 17β-estradiol, the major biologically active estrogen, can modulate cognition within a rapid time frame. Here we review recent studies that have begun to uncover the molecular and cellular framework which contributes to estrogens ability to rapidly modulate cognition.

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Apr
2014

The ability of a neuron to transduce extracellular signals into long lasting changes in neuronal morphology is central to its normal function. Increasing evidence shows that coordinated regulation of synaptic and nuclear signaling in response to NMDA receptor activation is crucial for long term memory, synaptic tagging, and epigenetic signaling. Although mechanisms have been proposed for synapse-to-nuclear communication, it is unclear how signaling is coordinated at both subcompartments.

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Dec
1969

Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function.

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Oct
2012

The dendritic field of a neuron, which is determined by both dendritic architecture and synaptic strength, defines the synaptic input of a cell. Once established, a neuron's dendritic field is thought to remain relatively stable throughout a cell's lifetime. Perturbations in a dendritic structure or excitatory tone of a cell and thus its dendritic field are cellular alterations thought to be correlated with a number of psychiatric disorders.

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Aug
2012

Deficits in social and communication behaviors are common features of a number of neurodevelopmental disorders. However, the molecular and cellular substrates of these higher order brain functions are not well understood. Here we report that specific alterations in social and communication behaviors in mice occur as a result of loss of the EPAC2 gene, which encodes a protein kinase A-independent cAMP target.

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Dec
1969

The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and differentially regulated, little is known about mechanisms that selectively maintain basal dendrites. Here we identified a role for the Ras/Epac2 pathway in maintaining basal dendrite complexity of cortical neurons.

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Aug
2012

Estrogens have been shown to exert powerful effects on cognitive behaviors mediated by several areas of the brain including the cortex. Remodeling of spiny synapses is a key step in the rewiring of neuronal circuitry thought to underlie the processing and storage of information in the forebrain. Whereas estrogen has been shown to regulate synapse structure and function, we are only just starting to understand the molecular and cellular underpinnings of how estrogens can modulate neuronal circuits.

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Nov
2011

Rapid actions of estrogens were first described >40 years ago. However, the importance of rapid estrogen-mediated actions in the CNS is only now becoming apparent. Several lines of evidence demonstrate that rapid estrogen-mediated signaling elicits potent effects on molecular and cellular events, resulting in the "fine-tuning" of neuronal circuitry.

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Jul
2011

Dendritic spines are the sites of the majority of excitatory connections within the brain, and form the post-synaptic compartment of synapses. These structures are rich in actin and have been shown to be highly dynamic. In response to classical Hebbian plasticity as well as neuromodulatory signals, dendritic spines can change shape and number, which is thought to be critical for the refinement of neural circuits and the processing and storage of information within the brain.

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Dec
1969

Estrogens have multiple actions in the brain including modulating synaptic plasticity, connectivity, and cognitive behaviors. While the classical view of estrogens are as endocrine signals, whose effects manifest via the regulation of gene transcription, mounting evidence has been presented demonstrating that estrogens have rapid effects within specific areas of the brain. The emergence that 17 β-estradiol can be produced locally in the brain which can elicit rapid (within minutes) cellular responses has led to its classification as a neurosteroid.

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Feb
2011

In the mammalian forebrain, most glutamatergic excitatory synapses occur on small dendritic protrusions called dendritic spines. Dendritic spines are highly plastic and can rapidly change morphology in response to numerous stimuli. This dynamic remodeling of dendritic spines is thought to be critical for information processing, memory and cognition.

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Oct
2010

Brain-synthesized estrogen has been shown to influence synaptic structure, function, and cognitive processes. However, the molecular mechanisms underlying the rapid effects of estrogen on the dendritic spines of cortical neurons are not clear. Estrogen receptor β (ERβ) is expressed in cortical neurons, and ERβ knock-out mice display impaired performance in cortically mediated processes, suggesting that signaling via this receptor has profound effects on cortical neuron function.

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Mar
2010

Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo.

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Nov
2009

The 5-HT(2A) serotonin receptor is the most abundant serotonin receptor subtype in the cortex and is predominantly expressed in pyramidal neurons. The 5-HT(2A) receptor is a target of several hallucinogens, antipsychotics, anxiolytics, and antidepressants, and it has been associated with several psychiatric disorders, conditions that are also associated with aberrations in dendritic spine morphogenesis. However, the role of 5-HT(2A) receptors in regulating dendritic spine morphogenesis in cortical neurons is unknown.

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Oct
2009

Neuronal morphology plays an essential role in neuronal function. The establishment and maintenance of neuronal morphology is intimately linked to the actin cytoskeleton; however, the molecular mechanisms that regulate changes in neuronal morphology are poorly understood. Here we identify a novel myosin-Va (MyoVa)-interacting protein, RILPL2, which regulates cellular morphology.

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Oct
2009

Dynamic remodeling of spiny synapses is crucial for cortical circuit development, refinement and plasticity, whereas abnormal morphogenesis is associated with neuropsychiatric disorders. We found that activation of Epac2, a PKA-independent cAMP target and Rap guanine-nucleotide exchange factor (GEF), in cultured rat cortical neurons induced spine shrinkage, increased spine motility, removed synaptic GluR2/3-containing AMPA receptors and depressed excitatory transmission, whereas its inhibition promoted spine enlargement and stabilization. Epac2 was required for dopamine D1-like receptor-dependent spine shrinkage and GluR2 removal from spines.

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Oct
2009

Dopamine receptors function to control many aspects of motor control and other forms of behaviour in both vertebrates and invertebrates. They can be divided into two main groups (D(1) and D(2)) based on sequence similarity, ligand affinity and effector coupling. However, little is known about the pharmacology and functionality of dopamine receptors in the deuterostomian invertebrates, such as the cephalochordate amphioxus (Branchiostoma floridae) which has recently been placed as the most basal of all the chordates.

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Mar
2009

Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction.

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Jan
2009

Despite intense attention, the mechanisms regulating dendritic spine structure remain elusive. In this issue of Neuron, Jaworski and colleagues explore the morphological consequences of periodic spine incursions of dynamic microtubules and their associated protein, EB3. Microtubules, long thought to be absent from dendritic spines, are capable of controlling spine morphology, opening up a new line of investigation into mechanisms of spine plasticity and maintenance.

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Sep
2008

Cortical information storage requires combined changes in connectivity and synaptic strength between neurons, but the signaling mechanisms underlying this two-step wiring plasticity are unknown. Because acute 17beta-estradiol (E2) modulates cortical memory, we examined its effects on spine morphogenesis, AMPA receptor trafficking, and GTPase signaling in cortical neurons. Acute E2 application resulted in a rapid, transient increase in spine density, accompanied by temporary formation of silent synapses through reduced surface GluR1.

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Sep
2008

Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity and behavior, and its malfunction underlies many neurodevelopmental and psychiatric disorders. However, the molecular mechanisms that control dendritic spine morphogenesis have only recently emerged. We summarize recent work that has revealed an important connection between calcium/calmodulin-dependent kinases (CaMKs) and guanine-nucleotide-exchange factors (GEFs) that activate the small GTPase Rac (RacGEFs) in controlling dendritic spine morphogenesis.

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Jun
2008

Remodeling of central excitatory synapses is crucial for synapse maturation and plasticity, and contributes to neurodevelopmental and psychiatric disorders. Remodeling of dendritic spines and the associated synapses has been postulated to require the coordination of adhesion with spine morphology and stability; however, the molecular mechanisms that functionally link adhesion molecules with regulators of dendritic spine morphology are mostly unknown. Here, we report that spine size and N-cadherin content are tightly coordinated.

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Nov
2007

Activity-dependent rapid structural and functional modifications of central excitatory synapses contribute to synapse maturation, experience-dependent plasticity, and learning and memory and are associated with neurodevelopmental and psychiatric disorders. However, the signal transduction mechanisms that link glutamate receptor activation to intracellular effectors that accomplish structural and functional plasticity are not well understood. Here we report that NMDA receptor activation in pyramidal neurons causes CaMKII-dependent phosphorylation of the guanine-nucleotide exchange factor (GEF) kalirin-7 at residue threonine 95, regulating its GEF activity, leading to activation of small GTPase Rac1 and rapid enlargement of existing spines.

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Sep
2007

Cadherin-mediated interactions are integral to synapse formation and potentiation. Here we show that N-cadherin is required for memory formation and regulation of a subset of underlying biochemical processes. N-cadherin antagonistic peptide containing the His-Ala-Val motif (HAV-N) transiently disrupted hippocampal N-cadherin dimerization and impaired the formation of long-term contextual fear memory while sparing short-term memory, retrieval, and extinction.

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Jun
2005

Nongenomic response pathways mediate many of the rapid actions of steroid hormones, but the mechanisms underlying such responses remain controversial. In some cases, cell-surface expression of classical nuclear steroid receptors has been suggested to mediate these effects, but, in a few instances, specific G-protein-coupled receptors (GPCRs) have been reported to be responsible. Here, we describe the activation of a novel, neuronally expressed Drosophila GPCR by the insect ecdysteroids ecdysone (E) and 20-hydroxyecdysone (20E).

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