Abl2:cortactin interactions regulate dendritic spine stability via control of a stable filamentous actin pool

AbstractDendritic spines are enriched with stable and dynamic actin filaments, which determine their structure and shape. Disruption of the Abl2/Arg nonreceptor tyrosine kinase in mice compromises spine stability and size. We provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. Using fluorescence recovery after photobleaching of GFP-actin, we find that disruption of Abl2:cortactin interactions eliminates stable actin filaments in dendritic spines, significantly reducing spine density. A subset of spines remaining after Abl2 depletion retain their stable actin pool and undergo activity-dependent spine enlargement associated with increased cortactin levels. Finally, tonic increases in synaptic activity rescue spine loss upon Abl2 depletion by promoting cortactin enrichment in vulnerable spines. Together, our findings strongly suggest Abl2:cortactin interactions promote spine stability by maintaining pools of stable actin filaments in spines.

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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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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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Activity-dependent regulation of dendritic spine density on cortical pyramidal neurons in organotypic slice cultures

Journal of Neurobiology ◽

10.1002/neu.480251202 ◽

1994 ◽

Vol 25 (12) ◽

pp. 1483-1493 ◽

Cited By ~ 24

Author(s):

Casey M. Annis ◽

Diane K. O'Dowd ◽

Richard T. Robertson

Keyword(s):

Dendritic Spine ◽

Pyramidal Neurons ◽

Spine Density ◽

Dendritic Spine Density ◽

Cortical Pyramidal Neurons ◽

Organotypic Slice Cultures ◽

Activity Dependent

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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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Targeting of NF-κB to Dendritic Spines is Required for Synaptic Signaling and Spine Development

10.1101/283879 ◽

2018 ◽

Author(s):

Erica C. Dresselhaus ◽

Matthew C.H. Boersma ◽

Mollie K. Meffert

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Dendritic Spines ◽

Brain Plasticity ◽

Spatial Localization ◽

Synaptic Activity ◽

Wild Type ◽

Spine Development ◽

Response Expression ◽

Activity Dependent

ABSTRACTLong-term forms of brain plasticity share a requirement for changes in gene expression induced by neuronal activity. Mechanisms that determine how the distinct and overlapping functions of multiple activity-responsive transcription factors, including nuclear factor kappa B (NF-κB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-κB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine-enrichment (ΔSEp65) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or ΔSEp65 both rescue NF-κB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-κB are selectively impaired in NF-κB-dependent gene expression induced by elevated excitatory synaptic stimulation (bicuculline or glycine). We used the setting of excitatory synaptic activity during development that produces NF-κB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-κB in an activity-dependent response. Expression of wild-type p65, but not ΔSEp65, is capable of rescuing spine density to normal levels in p65-deficient pyramidal neurons. Collectively, these data reveal that spatial localization in dendritic spines contributes unique capacities to the NF-κB transcription factor in synaptic activity-dependent responses.SIGNIFICANCE STATEMENTExtensive research has established a model in which the regulation of neuronal gene expression enables enduring forms of plasticity and learning. However, mechanisms imparting stimulus-specificity to gene regulation, insuring biologically appropriate responses, remain incompletely understood. NF-κB is a potent transcription factor with evolutionarily-conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-κB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-κB has discrete functions is unknown. This study reveals that NF-κB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-κB activation by synaptic stimulation and normal dendritic spine development. These results support spatial localization at synapses as a key variable mediating selective stimulus-response coupling.

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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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Impact of Time-Dependent Changes in Spine Density and Spine Shape on the Input-Output Properties of a Dendritic Branch: A Computational Study

Journal of Neurophysiology ◽

10.1152/jn.00373.2004 ◽

2005 ◽

Vol 93 (4) ◽

pp. 2073-2089 ◽

Cited By ~ 23

Author(s):

D. W. Verzi ◽

M. B. Rheuben ◽

S. M. Baer

Keyword(s):

Computational Study ◽

Long Term Potentiation ◽

Synaptic Activity ◽

High Frequency Stimulation ◽

Spine Density ◽

Dendritic Branch ◽

Input Output ◽

Stem Resistance ◽

Rate Of Increase ◽

Activity Dependent

Populations of dendritic spines can change in number and shape quite rapidly as a result of synaptic activity. Here, we explore the consequences of such changes on the input–output properties of a dendritic branch. We consider two models: one for activity-dependent spine densities and the other for calcium-mediated spine-stem restructuring. In the activity-dependent density model we find that for repetitive synaptic input to passive spines, changes in spine density remain local to the input site. For excitable spines, the spine density increases both inside and outside the input region. When the spine stem resistances are relatively high, the transition to higher dendritic output is abrupt; when low, the rate of increase is gradual and resembles long-term potentiation. In the second model, spine density is held constant, but the stem dimensions are allowed to change as a result of stimulation-induced calcium influxes. The model is formulated so that a moderate amount of synaptic activation results in spine stem elongation, whereas high levels of activation result in stem shortening. Under these conditions, passive spines receiving modest stimulation progressively increase their spine stem resistance and head potentials, but little change occurs in the dendritic output. For excitable spines, modest stimulation frequencies cause a lengthening of both stimulated and neighboring spines and the stimulus eventually propagates. High-frequency stimulation that causes spines to shorten in the stimulated region decreases the amplitude of the dendritic output slightly or drastically, depending on initial spine densities and stem resistances.

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Activity-dependent expression of reporter proteins at dendritic spines for synaptic activity mapping and optogenetic stimulation

10.1101/095984 ◽

2016 ◽

Author(s):

Francesco Gobbo ◽

Laura Marchetti ◽

Claudia Alia ◽

Stefano Luin ◽

Antonino Cattaneo

Keyword(s):

Dendritic Spines ◽

Cognitive Disorders ◽

Synaptic Activity ◽

Regulatory Sequences ◽

Synaptic Connections ◽

Optogenetic Stimulation ◽

Reporter Proteins ◽

Activity Dependent ◽

The Brain ◽

Spine Number

Increasing evidence points to the importance of dendritic spines in the formation and allocation of memories, and alterations of spine number and physiology are associated to memory and cognitive disorders. Synaptic connections and pathways constitute the physical substrate that conveys information in the brain, and different combinations of active synaptic connections are believed to be responsible for the encoding of specific memories. In addition, modifications of the activity of such subsets of synapses are believed to be crucial for memory establishment, but a way to directly test this hypothesis, by selectively controlling the activity of potentiated spines, is currently lagging behind. Therefore it would be important to develop methods to tag active synapses for mapping functionally active connections and to selectively stimulate or interfere with active synapses. Here we introduce an approach to express light-sensitive membrane channels at synapses in an activity-dependent way by means of RNA and protein regulatory sequences. This approach is based on the local expression of reporter proteins, including optogenetic probes, at activated synapses and will allow the mapping of previously active synapses and the re-activation of the neuron only at these sites. This will allow extending the investigation of memory processes beyond the current neuron tagging technologies, whose resolution is limited at the cellular scale. Thus, it will be possible to unveil and recall the synaptic engram out of the global set of synapses.

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