Effect of Phosphorylated Tau on Cortical Pyramidal Neuron Morphology during Hibernation

Abstract The dendritic spines of pyramidal cells are the main postsynaptic target of excitatory glutamatergic synapses. Morphological alterations have been described in hippocampal dendritic spines during hibernation—a state of inactivity and metabolic depression that occurs via a transient neuronal tau hyperphosphorylation. Here, we have used the hibernating Syrian hamster to investigate the effect of hyperphosphorylated tau regarding neocortical neuronal structure. In particular, we examined layer Va pyramidal neurons. Our results indicate that hibernation does not promote significant changes in dendritic spine density. However, tau hyperphosphorylated neurons show a decrease in complexity, an increase in the tortuosity of the apical dendrites, and an increase in the diameter of the basal dendrites. Tau protein hyperphosphorylation and aggregation have been associated with loss or alterations of dendritic spines in neurodegenerative diseases, such as Alzheimer’s disease (AD). Our results may shed light on the correlation between tau hyperphosphorylation and the neuropathological processes in AD. Moreover, we observed changes in the length and area of the apical and basal dendritic spines during hibernation regardless of tau hyperphosphorylation. The morphological changes observed here also suggest region specificity, opening up debate about a possible relationship with the differential brain activity registered in these regions in previous studies.

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Lack of change in CA1 dendritic spine density or clustering in rats following training on a radial-arm maze task

Wellcome Open Research ◽

10.12688/wellcomeopenres.15745.2 ◽

2020 ◽

Vol 5 ◽

pp. 68

Author(s):

Emma Craig ◽

Christopher M. Dillingham ◽

Michal M. Milczarek ◽

Heather M. Phillips ◽

Moira Davies ◽

...

Keyword(s):

Dendritic Spines ◽

Pyramidal Neurons ◽

Memory Load ◽

Spatial Location ◽

Memory Formation ◽

Spatial Task ◽

Radial Arm Maze ◽

Nearest Neighbour ◽

Spine Density ◽

Ca1 Region

Background: Neuronal plasticity is thought to underlie learning and memory formation. The density of dendritic spines in the CA1 region of the hippocampus has been repeatedly linked to mnemonic processes. Both the number and spatial location of the spines, in terms of proximity to nearest neighbour, have been implicated in memory formation. To examine how spatial training impacts synaptic structure in the hippocampus, Lister-Hooded rats were trained on a hippocampal-dependent spatial task in the radial-arm maze. Methods: One group of rats were trained on a hippocampal-dependent spatial task in the radial arm maze. Two further control groups were included: a yoked group which received the same sensorimotor stimulation in the radial-maze but without a memory load, and home-cage controls. At the end of behavioural training, the brains underwent Golgi staining. Spines on CA1 pyramidal neuron dendrites were imaged and quantitatively assessed to provide measures of density and distance from nearest neighbour. Results: There was no difference across behavioural groups either in terms of spine density or in the clustering of dendritic spines. Conclusions: Spatial learning is not always accompanied by changes in either the density or clustering of dendritic spines on the basal arbour of CA1 pyramidal neurons when assessed using Golgi imaging.

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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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Evidence of calcium-permeable AMPA receptors in dendritic spines of CA1 pyramidal neurons

Journal of Neurophysiology ◽

10.1152/jn.00578.2013 ◽

2014 ◽

Vol 112 (2) ◽

pp. 263-275 ◽

Cited By ~ 9

Author(s):

Hayley A. Mattison ◽

Ashish A. Bagal ◽

Michael Mohammadi ◽

Nisha S. Pulimood ◽

Christian G. Reich ◽

...

Keyword(s):

Dendritic Spines ◽

Ampa Receptors ◽

Pyramidal Neurons ◽

Calcium Influx ◽

Hippocampal Slices ◽

Pyramidal Cells ◽

Stratum Radiatum ◽

Acute Hippocampal Slices ◽

Cultured Slices ◽

Apical Dendrites

GluA2-lacking, calcium-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) have unique properties, but their presence at excitatory synapses in pyramidal cells is controversial. We have tested certain predictions of the model that such receptors are present in CA1 cells and show here that the polyamine spermine, but not philanthotoxin, causes use-dependent inhibition of synaptically evoked excitatory responses in stratum radiatum, but not s. oriens, in cultured and acute hippocampal slices. Stimulation of single dendritic spines by photolytic release of caged glutamate induced an N-methyl-d-aspartate receptor-independent, use- and spermine-sensitive calcium influx only at apical spines in cultured slices. Bath application of glutamate also triggered a spermine-sensitive influx of cobalt into CA1 cell dendrites in s. radiatum. Responses of single apical, but not basal, spines to photostimulation displayed prominent paired-pulse facilitation (PPF) consistent with use-dependent relief of cytoplasmic polyamine block. Responses at apical dendrites were diminished, and PPF was increased, by spermine. Intracellular application of pep2m, which inhibits recycling of GluA2-containing AMPARs, reduced apical spine responses and increased PPF. We conclude that some calcium-permeable, polyamine-sensitive AMPARs, perhaps lacking GluA2 subunits, are present at synapses on apical dendrites of CA1 pyramidal cells, which may allow distinct forms of synaptic plasticity and computation at different sets of excitatory inputs.

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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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Conditional deletion of ROCK2 induces anxiety-like behaviors and alters dendritic spine density and morphology on CA1 pyramidal neurons

Molecular Brain ◽

10.1186/s13041-021-00878-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Audrey J. Weber ◽

Ashley B. Adamson ◽

Kelsey M. Greathouse ◽

Julia P. Andrade ◽

Cameron D. Freeman ◽

...

Keyword(s):

Dendritic Spine ◽

Basolateral Amygdala ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

Spine Density ◽

Control Of Gene Expression ◽

Spine Morphology ◽

Dendritic Spine Morphology ◽

Morphometry Analysis ◽

Apical Dendrites

AbstractRho-associated kinase isoform 2 (ROCK2) is an attractive drug target for several neurologic disorders. A critical barrier to ROCK2-based research and therapeutics is the lack of a mouse model that enables investigation of ROCK2 with spatial and temporal control of gene expression. To overcome this, we generated ROCK2fl/fl mice. Mice expressing Cre recombinase in forebrain excitatory neurons (CaMKII-Cre) were crossed with ROCK2fl/fl mice (Cre/ROCK2fl/fl), and the contribution of ROCK2 in behavior as well as dendritic spine morphology in the hippocampus, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) was examined. Cre/ROCK2fl/fl mice spent reduced time in the open arms of the elevated plus maze and increased time in the dark of the light–dark box test compared to littermate controls. These results indicated that Cre/ROCK2fl/fl mice exhibited anxiety-like behaviors. To examine dendritic spine morphology, individual pyramidal neurons in CA1 hippocampus, mPFC, and the BLA were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and neuronal 3D reconstructions for morphometry analysis. In dorsal CA1, Cre/ROCK2fl/fl mice displayed significantly increased thin spine density on basal dendrites and reduced mean spine head volume across all spine types on apical dendrites. In ventral CA1, Cre/ROCK2fl/fl mice exhibited significantly increased spine length on apical dendrites. Spine density and morphology were comparable in the mPFC and BLA between both genotypes. These findings suggest that neuronal ROCK2 mediates spine density and morphology in a compartmentalized manner among CA1 pyramidal cells, and that in the absence of ROCK2 these mechanisms may contribute to anxiety-like behaviors.

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Electron microscopy of the somatic sensory cortex of the cat III. The fine structure layers III to VI

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1970.0005 ◽

1970 ◽

Vol 257 (812) ◽

pp. 23-28 ◽

Cited By ~ 18

Keyword(s):

Fine Structure ◽

Dendritic Spines ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

Progressive Increase ◽

Sensory Cortex ◽

Axon Terminals ◽

Clear Cut ◽

Unmyelinated Axons ◽

Somatic Sensory Cortex

Variations in the fine structure of layers III to VI of the somatic sensory cortex have been described. Layers III and IV may be readily distinguished from one another and from layers V and VI, but within the latter two layers there is such a slow gradient of change that no clear-cut line of junction can be drawn between them. Layer III is characterized by the presence of many large apical dendrites ascending vertically through it from pyramidal cells in all layers to reach layer I. In parallel with these are many small unmyelinated axons which contain flattened synaptic vesicles and terminate on transversely orientated dendrites in symmetrical synaptic complexes. The remainder of the neuropil is filled by large numbers of dendritic spines receiving axon terminals which contain spherical vesicles and which terminate asymmetrically. In layer IV there is a marked increase in the number of small myelinated axons ascending from below and ramifying within it. Embedded in the neuropil among these are many small non-pyramidal neurons whose somata and small, irregular dendrites are covered in axon terminals. Also present, and particularly concentrated at the junction with layer III, is a meshwork of fine unmyelinated axons which contain flattened vesicles and terminate in an en passant manner as symmetrical type synapses. Most of these axons are orientated transversely. A larger axon terminal which ends in asymmetrical complexes on small dendritic shafts and spines and which may be the terminal of thalamo-cortical axons is only found in any quantity in this layer. On descending into layers V and VI there is a progressive increase in the number of large myelinated fibres and glial cells, and a progressive diminution of neuronal elements, particularly dendritic spines. Some large non-pyramidal cells resembling the smaller ones on layer IV are present in layer VI.

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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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Human cortical pyramidal neurons: From spines to spikes via models

10.1101/267898 ◽

2018 ◽

Cited By ~ 2

Author(s):

Guy Eyal ◽

Matthias B. Verhoog ◽

Guilherme Testa-Silva ◽

Yair Deitcher ◽

Ruth Benavides-Piccione ◽

...

Keyword(s):

Dendritic Spines ◽

Cortical Neurons ◽

Pyramidal Neurons ◽

Temporal Cortex ◽

Pyramidal Cells ◽

Physiological Data ◽

Excitatory Synapses ◽

Basal Dendrites ◽

Cortical Pyramidal Neurons ◽

Dendritic Branches

AbstractWe present the first-ever detailed models of pyramidal cells from human neocortex, including models on their excitatory synapses, dendritic spines, dendritic NMDA- and somatic/axonal- Na+ spikes that provided new insights into signal processing and computational capabilities of these principal cells. Six human layer 2 and layer 3 pyramidal cells (HL2/L3 PCs) were modeled, integrating detailed anatomical and physiological data from both fresh and post mortem tissues from human temporal cortex. The models predicted particularly large AMPA- and NMDA- conductances per synaptic contact (0.88 nS and 1.31nS, respectively) and a steep dependence of the NMDA-conductance on voltage. These estimates were based on intracellular recordings from synaptically-connected HL2/L3 pairs, combined with extra-cellular current injections and use of synaptic blockers. A large dataset of high-resolution reconstructed HL2/L3 dendritic spines provided estimates for the EPSPs at the spine head (12.7 ± 4.6 mV), spine base (9.7 ± 5.0 mV) and soma (0.3 ± 0.1 mV), and for the spine neck resistance (50 – 80 MΩ). Matching the shape and firing pattern of experimental somatic Na+-spikes provided estimates for the density of the somatic/axonal excitable membrane ion channels, predicting that 134 ± 28 simultaneously activated HL2/L3- HL2/L3 synapses are required for generating (with 50% probability) a somatic Na+ spike. Dendritic NMDA spikes were triggered in the model when 20 ± 10 excitatory spinous synapses were simultaneously activated on individual dendritic branches. The particularly large number of basal dendrites in HL2/L3 PCs and the distinctive cable elongation of their terminals imply that ~25 NMDA- spikes could be generated independently and simultaneously in these cells, as compared to ~14 in L2/3 PCs from the rat temporal cortex. These multi-sites nonlinear signals, together with the large (~30,000) excitatory synapses/cell, equip human L2/L3 PCs with enhanced computational capabilities. Our study provides the most comprehensive model of any human neuron to-date demonstrating the biophysical and computational distinctiveness of human cortical neurons.

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Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology and Hebbian plasticity in the mouse hippocampus

10.1101/320507 ◽

2018 ◽

Author(s):

Thiago C. Moulin ◽

Lyvia L. Petiz ◽

Danielle Rayêe ◽

Jessica Winne ◽

Roberto G. Maia ◽

...

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Ex Vivo ◽

Morphological Changes ◽

Spine Density ◽

Optogenetic Stimulation ◽

Light Pulses ◽

Ca1 Region ◽

Hebbian Plasticity

AbstractProlonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

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Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

eLife ◽

10.7554/elife.15106 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 28

Author(s):

Sonia Afroz ◽

Julie Parato ◽

Hui Shen ◽

Sheryl Sue Smith

Keyword(s):

Actin Cytoskeleton ◽

Dendritic Spines ◽

Gabaa Receptors ◽

Pyramidal Cells ◽

Spine Density ◽

Inhibitory Receptor ◽

Wild Type ◽

Nmdar Activation ◽

Cytoskeleton Remodeling ◽

Synaptic Pruning

Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4βδ GABAA receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4βδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4βδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4βδ GABARs. In their absence, pruning is prevented and cognition is not optimal.

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