Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

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Dendritic Spine Initiation in Brain Development, Learning and Diseases and Impact of BAR-Domain Proteins

Cells ◽

10.3390/cells10092392 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2392 ◽

Cited By ~ 1

Author(s):

Pushpa Khanal ◽

Pirta Hotulainen

Keyword(s):

Brain Development ◽

Dendritic Spines ◽

Dendritic Spine ◽

Molecular Mechanisms ◽

Neurological Diseases ◽

Spine Density ◽

Bar Domain ◽

Neuronal Dendrites ◽

Bar Domain Proteins ◽

Before And After

Dendritic spines are small, bulbous protrusions along neuronal dendrites where most of the excitatory synapses are located. Dendritic spine density in normal human brain increases rapidly before and after birth achieving the highest density around 2–8 years. Density decreases during adolescence, reaching a stable level in adulthood. The changes in dendritic spines are considered structural correlates for synaptic plasticity as well as the basis of experience-dependent remodeling of neuronal circuits. Alterations in spine density correspond to aberrant brain function observed in various neurodevelopmental and neuropsychiatric disorders. Dendritic spine initiation affects spine density. In this review, we discuss the importance of spine initiation in brain development, learning, and potential complications resulting from altered spine initiation in neurological diseases. Current literature shows that two Bin Amphiphysin Rvs (BAR) domain-containing proteins, MIM/Mtss1 and SrGAP3, are involved in spine initiation. We review existing literature and open databases to discuss whether other BAR-domain proteins could also take part in spine initiation. Finally, we discuss the potential molecular mechanisms on how BAR-domain proteins could regulate spine initiation.

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Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

10.1101/065391 ◽

2016 ◽

Author(s):

Tharkika Nagendran ◽

Rylan S. Larsen ◽

Rebecca L. Bigler ◽

Shawn B. Frost ◽

Benjamin D. Philpot ◽

...

Keyword(s):

Dendritic Spines ◽

Dendritic Spine ◽

Pyramidal Neurons ◽

Spine Density ◽

Axon Injury ◽

Synaptic Remodeling ◽

Nerve Tracts ◽

Specific Increase ◽

Microfluidic Chambers

AbstractInjury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.

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Bergmann glial ensheathment of dendritic spines regulates synapse number without affecting spine motility

Neuron Glia Biology ◽

10.1017/s1740925x10000165 ◽

2010 ◽

Vol 6 (3) ◽

pp. 193-200 ◽

Cited By ~ 22

Author(s):

Jocelyn J. Lippman Bell ◽

Tamar Lordkipanidze ◽

Natalie Cobb ◽

Anna Dunaevsky

Keyword(s):

Purkinje Cell ◽

Dendritic Spines ◽

Dendritic Spine ◽

Adenoviral Vector ◽

Spine Density ◽

Dendritic Spine Density ◽

Spine Dynamics

In the cerebellum, lamellar Bergmann glial (BG) appendages wrap tightly around almost every Purkinje cell dendritic spine. The function of this glial ensheathment of spines is not entirely understood. The development of ensheathment begins near the onset of synaptogenesis, when motility of both BG processes and dendritic spines are high. By the end of the synaptogenic period, ensheathment is complete and motility of the BG processes decreases, correlating with the decreased motility of dendritic spines. We therefore have hypothesized that ensheathment is intimately involved in capping synaptogenesis, possibly by stabilizing synapses. To test this hypothesis, we misexpressed GluR2 in an adenoviral vector in BG towards the end of the synaptogenic period, rendering the BG α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) Ca2+-impermeable and causing glial sheath retraction. We then measured the resulting spine motility, spine density and synapse number. Although we found that decreasing ensheathment at this time does not alter spine motility, we did find a significant increase in both synaptic pucta and dendritic spine density. These results indicate that consistent spine coverage by BG in the cerebellum is not necessary for stabilization of spine dynamics, but is very important in the regulation of synapse number.

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Hippocampal CA1 Pyramidal Neurons ofMecp2Mutant Mice Show a Dendritic Spine Phenotype Only in the Presymptomatic Stage

Neural Plasticity ◽

10.1155/2012/976164 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 19

Author(s):

Christopher A. Chapleau ◽

Elena Maria Boggio ◽

Gaston Calfa ◽

Alan K. Percy ◽

Maurizio Giustetto ◽

...

Keyword(s):

Dendritic Spines ◽

Dendritic Spine ◽

Pyramidal Neurons ◽

Mutant Mice ◽

Spine Density ◽

Ca1 Pyramidal Neurons ◽

Dendritic Spine Density ◽

Presymptomatic Stage ◽

Deficient Mice

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations inMECP2, is the leading cause of intellectual disabilities in women. Neurons inMecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus ofMecp2tm1.1Jaemale mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1stratum radiatumof symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomaticMecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

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An Image Analysis Algorithm for Dendritic Spines

Neural Computation ◽

10.1162/089976602753712945 ◽

2002 ◽

Vol 14 (6) ◽

pp. 1283-1310 ◽

Cited By ~ 100

Author(s):

Ingrid Y. Y. Koh ◽

W. Brent Lindquist ◽

Karen Zito ◽

Esther A. Nimchinsky ◽

Karel Svoboda

Keyword(s):

Neural Networks ◽

Time Series ◽

Dendritic Spines ◽

Dendritic Spine ◽

Time Series Data ◽

Neuronal Morphology ◽

Laser Scanning Microscopy ◽

Series Data ◽

Spine Length ◽

Spine Morphology

The structure of neuronal dendrites and their spines underlie the connectivity of neural networks. Dendrites, spines, and their dynamics are shaped by genetic programs as well as sensory experience. Dendritic structures and dynamics may therefore be important predictors of the function of neural networks. Based on new imaging approaches and increases in the speed of computation, it has become possible to acquire large sets of high-resolution optical micrographs of neuron structure at length scales small enough to resolve spines. This advance in data acquisition has not been accompanied by comparable advances in data analysis techniques; the analysis of dendritic and spine morphology is still accomplished largely manually. In addition to being extremely time intensive, manual analysis also introduces systematic and hard-to-characterize biases. We present a geometric approach for automatically detecting and quantifying the three-dimensional structure of dendritic spines from stacks of image data acquired using laser scanning microscopy. We present results on the measurement of dendritic spine length, volume, density, and shape classification for both static and timelapse images of dendrites of hippocampal pyramidal neurons. For spine length and density, the automated measurements in static images are compared with manual measurements. Comparisons are also made between automated and manual spine length measurements for a time-series data set. The algorithm performs well compared to a human analyzer, especially on time-series data. Automated analysis of dendritic spine morphology will enable objective analysis of large morphological data sets. The approaches presented here are generalizable to other aspects of neuronal morphology.

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Toward a Brain-Inspired Developmental Neural Network Based on Dendritic Spine Dynamics

Neural Computation ◽

10.1162/neco_a_01448 ◽

2021 ◽

pp. 1-18

Author(s):

Feifei Zhao ◽

Yi Zeng ◽

Jun Bai

Keyword(s):

Neural Network ◽

Dendritic Spines ◽

Dendritic Spine ◽

Synapse Formation ◽

Dynamic Structure ◽

Classification Performance ◽

Synaptic Activity ◽

Data Sets ◽

Spine Density ◽

Spine Dynamics

Abstract Neural networks with a large number of parameters are prone to overfitting problems when trained on a relatively small training set. Introducing weight penalties of regularization is a promising technique for solving this problem. Taking inspiration from the dynamic plasticity of dendritic spines, which plays an important role in the maintenance of memory, this letter proposes a brain-inspired developmental neural network based on dendritic spine dynamics (BDNN-dsd). The dynamic structure changes of dendritic spines include appearing, enlarging, shrinking, and disappearing. Such spine plasticity depends on synaptic activity and can be modulated by experiences—in particular, long-lasting synaptic enhancement/suppression (LTP/LTD), coupled with synapse formation (or enlargement)/elimination (or shrinkage), respectively. Subsequently, spine density characterizes an approximate estimate of the total number of synapses between neurons. Motivated by this, we constrain the weight to a tunable bound that can be adaptively modulated based on synaptic activity. Dynamic weight bound could limit the relatively redundant synapses and facilitate the contributing synapses. Extensive experiments demonstrate the effectiveness of our method on classification tasks of different complexity with the MNIST, Fashion MNIST, and CIFAR-10 data sets. Furthermore, compared to dropout and L2 regularization algorithms, our method can improve the network convergence rate and classification performance even for a compact network.

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Sex differences in dendritic spine density and morphology in auditory and visual cortices in adolescence and adulthood

Scientific Reports ◽

10.1038/s41598-020-65942-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Emily M. Parker ◽

Nathan L. Kindja ◽

Claire E. J. Cheetham ◽

Robert A. Sweet

Keyword(s):

Sex Differences ◽

Dendritic Spines ◽

Dendritic Spine ◽

Brain Regions ◽

Spine Density ◽

Female Mice ◽

Dendritic Spine Density ◽

Layer 4 ◽

Visual Cortices ◽

Mushroom Spines

AbstractDendritic spines are small protrusions on dendrites that endow neurons with the ability to receive and transform synaptic input. Dendritic spine number and morphology are altered as a consequence of synaptic plasticity and circuit refinement during adolescence. Dendritic spine density (DSD) is significantly different based on sex in subcortical brain regions associated with the generation of sex-specific behaviors. It is largely unknown if sex differences in DSD exist in auditory and visual brain regions and if there are sex-specific changes in DSD in these regions that occur during adolescent development. We analyzed dendritic spines in 4-week-old (P28) and 12-week-old (P84) male and female mice and found that DSD is lower in female mice due in part to fewer short stubby, long stubby and short mushroom spines. We found striking layer-specific patterns including a significant age by layer interaction and significantly decreased DSD in layer 4 from P28 to P84. Together these data support the possibility of developmental sex differences in DSD in visual and auditory regions and provide evidence of layer-specific refinement of DSD over adolescent brain development.

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Preservation of dendritic spine morphology and postsynaptic signaling markers after treatment with solid lipid curcumin particles in the 5xFAD mouse model of Alzheimer’s disease

10.21203/rs.3.rs-27472/v1 ◽

2020 ◽

Author(s):

Panchanan Maiti ◽

Zackary L Bowers ◽

Ali Bourcier ◽

Jarod MOrse ◽

Gary L Dunbar

Keyword(s):

Alzheimer’S Disease ◽

Cognitive Function ◽

Dendritic Spines ◽

Dendritic Spine ◽

Amyloid Plaque ◽

Spine Density ◽

Solid Lipid ◽

Dendritic Spine Density ◽

Synaptic Markers ◽

5Xfad Mice

Abstract Background Synaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer’s disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice.Methods Six- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3 and the subicular complex (SC). Further, dendritic spine density of apical and basal branches were studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, kalirin-7, CREB and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP.Results We observed an increase number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary and secondary apical and basal branches were observed in PFC, EC, CA1, CA3 in both 6- and 12-month-old 5xFAD mice and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and post-synaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice.Conclusions Overall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, as well as preservation of dendritic spine density and synaptic markers in the 5xFAD mice.

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Hormonal regulation of adult hippocampal dendritic spine density

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100167883 ◽

1994 ◽

Vol 52 ◽

pp. 30-31

Author(s):

Catherine S. Woolley ◽

Bruce S. McEwen

Keyword(s):

Dendritic Spines ◽

Dendritic Spine ◽

Hormonal Regulation ◽

Dendritic Tree ◽

Pyramidal Cells ◽

Female Rat ◽

Spine Density ◽

Dendritic Spine Density ◽

Progesterone Treatment ◽

Lateral Branches

Dendritic spines cover the surface of a wide variety of neuronal types and are the postsynaptic sites of approximately 90% of the excitatory synapses formed in the central nervous system. Interestingly, changes in the morphology and/or density of dendritic spines have been shown to occur naturally, implying that they are a normal part of brain function. Even in the adult, dendritic spines are remarkably plastic. The hormonal state of an animal has been shown to be an important factor in regulation of dendritic spine density, both during development and in the adult.In the adult female rat, hippocampal CA1 pyramidal cells are particularly sensitive to variation in the circulating levels of the ovarian steroids, estradiol and progesterone. Removal of estradiol and progesterone by ovariectomy results in an approximately 50% decrease in the density of dendritic spines on the lateral branches of the apical dendritic tree. Treatment with estradiol can either protect against or reverse this decrease; subsequent progesterone treatment for as few as 5 hours significantly augments the effect of estradiol. By 18-24 hours following progesterone treatment, spine density returns to low values.

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Control of Dendritic Spine Morphological and Functional Plasticity by Small GTPases

Neural Plasticity ◽

10.1155/2016/3025948 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 39

Author(s):

Kevin M. Woolfrey ◽

Deepak P. Srivastava

Keyword(s):

Dendritic Spines ◽

Dendritic Spine ◽

Neuronal Development ◽

Structural Plasticity ◽

Small Gtpases ◽

Small Gtpase ◽

Abnormal Development ◽

Actin Dynamics ◽

Excitatory Synapses ◽

Spine Structure

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. Research over recent years has begun to unravel the complexities involved in the regulation of dendritic spine structure. The small GTPase family of proteins have emerged as key regulators of structural plasticity, linking extracellular signals with the modulation of dendritic spines, which potentially underlies their ability to influence cognition. Here we review a number of studies that examine how small GTPases are activated and regulated in neurons and furthermore how they can impact actin dynamics, and thus dendritic spine morphology. Elucidating this signalling process is critical for furthering our understanding of the basic mechanisms by which information is encoded in neural circuits but may also provide insight into novel targets for the development of effective therapies to treat cognitive dysfunction seen in a range of neurological disorders.

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