Human cortical pyramidal neurons: From spines to spikes via models

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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Neuronal primary cilia regulate pyramidal cell positioning to the deep and superficial sublayers in the hippocampal CA1

10.1101/2021.12.21.473383 ◽

2021 ◽

Author(s):

Juan Yang ◽

Liyan Qiu ◽

Xuanmao Chen

Keyword(s):

Pyramidal Cell ◽

Cortical Neurons ◽

Primary Cilia ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

Stratum Radiatum ◽

Neuronal Cilia ◽

Hippocampal Ca1 ◽

Cortical Pyramidal Neurons ◽

Cell Positioning

It is well-recognized that primary cilia regulate embryonic neurodevelopment, but little is known about their roles in postnatal neurodevelopment. The striatum pyramidal (SP) of hippocampal CA1 consists of superficial and deep sublayers, however, it is not well understood how early- and late-born pyramidal neurons position to two sublayers postnatally. Here we show that neuronal primary cilia emerge after CA1 pyramidal cells have reached SP, but before final neuronal positioning. The axonemes of primary cilia of early-born neurons point to the stratum oriens (SO), whereas late-born neuronal cilia orient toward the stratum radiatum (SR), reflecting an inside-out lamination pattern. Neuronal primary cilia in SP undergo marked changes in morphology and orientation from postnatal day 5 (P5) to P14, concurrent with pyramidal cell positioning to the deep and superficial sublayers and with neuronal maturation. Transgenic overexpression of Arl13B, a protein regulating ciliogenesis, not only elongates primary cilia and promotes earlier cilia protrusion, but also affects centriole positioning and cilia orientation in SP. The centrioles of late-born neurons migrate excessively to cluster at SP bottom before primary cilia protrusion and a reverse movement back to the main SP. Similarly, this pull-back movement of centriole/cilia is also identified on late-born cortical pyramidal neurons, although early- and late-born cortical neurons display the same cilia orientation. Together, this study provides the first evidence demonstrating that late-born pyramidal neurons exhibit a reverse movement for cell positioning, and primary cilia regulate pyramidal neuronal positioning to the deep and superficial sublayers in the hippocampus.

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Comparisons between Active Properties of Distal Dendritic Branches and Spines: Implications for Neuronal Computations

Journal of Cognitive Neuroscience ◽

10.1162/jocn.1989.1.3.273 ◽

1989 ◽

Vol 1 (3) ◽

pp. 273-286 ◽

Cited By ~ 29

Author(s):

Gordon M. Shepherd ◽

Thomas B. Woolf ◽

Nicholas T. Carnevale

Keyword(s):

Cortical Neurons ◽

Pyramidal Neurons ◽

General Purpose ◽

Distal Dendrite ◽

Brain Functions ◽

Cortical Pyramidal Neurons ◽

Network Simulations ◽

Logic Operations ◽

Dendritic Branches ◽

Higher Brain Functions

The specific contributions of distal dendrites to the computational properties of cortical neurons are little understood and are completely ignored in most network simulations of higher brain functions. Compartmental models, based on realistic estimates of morphology and physiology, provide a means for exploring these contributions. We have pursued analysis of a model of synaptic integration in a distal dendrite bearing four spines, using a new general-purpose simulation program called SABER. We have analyzed this model under the assumption that the dendrite contains sites of impulse-generating membrane, and we have compared its responses to synaptic activation with the case of impulse-generating membrane located instead in the spine heads, as previously reported. Both types of models generate basic logic operations, such as AND, OR, and AND-NOT gates. Active spine heads require lower excitatory synaptic conductances, but active branch segments lead to larger responses in the soma. The transients recorded near the soma give no evidence of their origin in either active branch or active spines, indicating that the interpretation of experimental recordings with regard to sites of distal active responses must be viewed with caution. The results suggest the hypothesis that a hierarchy of logic operations is virtually inherent in the branching structure of dendritic trees of cortical pyramidal neurons. Inclusion of these properties in representations of cortical neurons would greatly enhance the computational power of neural networks aimed at simulating higher brain functions.

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Two-Photon Microscopy of Single Molecules

Microscopy and Microanalysis ◽

10.1017/s1431927600036515 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 804-805

Author(s):

R. Yuste ◽

A. Majewska ◽

K. Holthoff ◽

K. Holthoff

Keyword(s):

Dendritic Spines ◽

Pyramidal Neurons ◽

Calcium Influx ◽

Pyramidal Cells ◽

Scattering Media ◽

Decay Kinetics ◽

Two Photon ◽

Photon Excitation ◽

Cortical Pyramidal Neurons ◽

Two Photon Excitation

Two-photon excitation has enabled investigators to image living cells in highly scattering media like the central nervous system (1). We have used a custom-built two-photon microscope to image dendritic spines from living cortical pyramidal neurons. Pyramidal cells form the majority of the neuron in the mammalian cortex and they receive practically all their synaptic contacts through dendritic spines. Dendritic spines are small (<1 μm diameter) appendages that have been practically inaccessible to physiological measurements until the application of two-photon excitation to their study (2). We have concentrated in two questions:A- Calcium compartmentalization of spines: Mechanisms of calcium decay kinetics.Dendritic spines can compartmentalize calcium (2). Although the mechanisms of calcium influx into spines have been explored (3), it is unknown what determines the calcium decay kinetics in spines. We investigate calcium dynamics in spines from rat CA1 pyramidal neurons in slices.

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Semaphorin3F Drives Dendritic Spine Pruning through Rho-GTPase Signaling

10.1101/2021.03.05.433425 ◽

2021 ◽

Author(s):

Bryce W. Duncan ◽

Vishwa Mohan ◽

Sarah D. Wade ◽

Young Truong ◽

Alexander Kampov-Polevoi ◽

...

Keyword(s):

Dendritic Spines ◽

Cortical Neurons ◽

Pyramidal Neurons ◽

Rho Gtpase ◽

Myosin Ii ◽

Actin Remodeling ◽

Semaphorin 3F ◽

Cortical Pyramidal Neurons ◽

Insight Into ◽

Spine Pruning

Dendritic spines of cortical pyramidal neurons are initially overproduced then remodeled substantially in the adolescent brain to achieve appropriate excitatory balance in mature circuits. Here we investigated the molecular mechanism of developmental spine pruning by Semaphorin 3F (Sema3F) and its holoreceptor complex, which consists of immunoglobulin-class adhesion molecule NrCAM, Neuropilin-2 (Npn2), and PlexinA3 (PlexA3) signaling subunits. Structure-function studies of the NrCAM-Npn2 interface showed that NrCAM stabilizes binding between Npn2 and PlexA3 necessary for Sema3F-induced spine pruning. Using a mouse neuronal culture system, we identified a dual signaling pathway for Sema3F-induced pruning, which involves activation of Tiam1-Rac1-PAK1-3 -LIMK1/2-Cofilin1 and RhoA-ROCK1/2-Myosin II in dendritic spines. Inhibitors of actin remodeling impaired spine collapse in the cortical neurons. Elucidation of these pathways expands our understanding of critical events that sculpt neuronal networks and may provide insight into how interruptions to these pathways could lead to spine dysgenesis in diseases such as autism, bipolar disorder, and schizophrenia.

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Comparing the electrophysiology and morphology of human and mouse layer 2/3 pyramidal neurons with Bayesian networks

10.1101/2020.06.02.130252 ◽

2020 ◽

Author(s):

Bojan Mihaljević ◽

Pedro Larrañaga ◽

Concha Bielza

Keyword(s):

Bayesian Networks ◽

Probabilistic Reasoning ◽

Pyramidal Neurons ◽

Temporal Cortex ◽

Input Resistance ◽

Cell Types ◽

Dendritic Arbor ◽

Basal Dendrites ◽

Morphological Variables ◽

Human And Mouse

ABSTRACTPyramidal neurons are the most common neurons in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. We compared human temporal cortex and mouse visual cortex pyramidal neurons from the Allen Cell Types Database in terms of their electrophysiology and basal dendrites’ morphology. We found that, among other differences, human pyramidal neurons had a higher threshold voltage, a lower input resistance, and a larger basal dendritic arbor. We learned Gaussian Bayesian networks from the data in order to identify correlations and conditional independencies between the variables and compare them between the species. We found strong correlations between electrophysiological and morphological variables in both species. One result is that, in human cells, dendritic arbor width had the strongest effect on input resistance after accounting for the remaining variables. Electrophysiological variables were correlated, in both species, even with morphological variables that are not directly related to dendritic arbor size or diameter, such as mean bifurcation angle and mean branch tortuosity. Contrary to previous results, cortical depth was correlated with both electrophysiological and morphological variables, and its effect on electrophysiological could not be explained in terms of the morphological variables. Overall, the correlations among the variables differed strikingly between human and mouse neurons. Besides identifying correlations and conditional independencies, the learned Bayesian networks might be useful for probabilistic reasoning regarding the morphology and electrophysiology of pyramidal neurons.

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Testosterone modulation of dendritic spines of somatosensory cortical pyramidal neurons

Brain Structure and Function ◽

10.1007/s00429-012-0465-7 ◽

2013 ◽

Vol 218 (6) ◽

pp. 1407-1417 ◽

Cited By ~ 11

Author(s):

Jeng-Rung Chen ◽

Tsyr-Jiuan Wang ◽

Seh-Hong Lim ◽

Yueh-Jan Wang ◽

Guo-Fang Tseng

Keyword(s):

Dendritic Spines ◽

Pyramidal Neurons ◽

Cortical Pyramidal Neurons

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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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Comparing basal dendrite branches in human and mouse hippocampal CA1 pyramidal neurons with Bayesian networks

Scientific Reports ◽

10.1038/s41598-020-73617-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Bojan Mihaljević ◽

Pedro Larrañaga ◽

Ruth Benavides-Piccione ◽

Javier DeFelipe ◽

Concha Bielza

Keyword(s):

Bayesian Networks ◽

Pyramidal Neurons ◽

Graphical Representation ◽

Data Set ◽

Ca1 Region ◽

Basal Dendrites ◽

Hippocampal Ca1 ◽

Dendritic Branches ◽

Branch Type ◽

Human And Mouse

Abstract Pyramidal neurons are the most common cell type in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. A recent study provided a unique set of human and mouse pyramidal neurons of the CA1 region of the hippocampus, and used it to compare the morphology of apical and basal dendritic branches of the two species. The study found inter-species differences in the magnitude of the morphometrics and similarities regarding their variation with respect to morphological determinants such as branch type and branch order. We use the same data set to perform additional comparisons of basal dendrites. In order to isolate the heterogeneity due to intrinsic differences between species from the heterogeneity due to differences in morphological determinants, we fit multivariate models over the morphometrics and the determinants. In particular, we use conditional linear Gaussian Bayesian networks, which provide a concise graphical representation of the independencies and correlations among the variables. We also extend the previous study by considering additional morphometrics and by formally testing whether a morphometric increases or decreases with the distance from the soma. This study introduces a multivariate methodology for inter-species comparison of morphology.

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Characterization of GABAA receptor function in human temporal cortical neurons

Journal of Neurophysiology ◽

10.1152/jn.1996.75.4.1458 ◽

1996 ◽

Vol 75 (4) ◽

pp. 1458-1471 ◽

Cited By ~ 35

Author(s):

J. W. Gibbs ◽

Y. F. Zhang ◽

C. Q. Kao ◽

K. L. Holloway ◽

K. S. Oh ◽

...

Keyword(s):

Patch Clamp ◽

Functional Properties ◽

Cortical Neurons ◽

Pyramidal Neurons ◽

Temporal Cortex ◽

Hill Coefficient ◽

Excitatory Postsynaptic Potential ◽

Adult Rat ◽

Postsynaptic Potential ◽

Resected Tissue

1. Surgically resected tissue from the tip of the human temporal lobe of seven patients undergoing temporal lobectomy was employed to study functional properties of GABAergic inhibition mediated through activation of GABAA receptors, using patch-clamp recording techniques in acutely isolated neurons and in slices of human temporal cortex. 2. Human temporal cortical pyramidal neurons from surgically resected tissue could be acutely isolated with the use of conventional methods. These neurons appeared normal in morphology, in their intrinsic membrane properties, and in their response to application of exogenous gamma-aminobutyric acid (GABA). 3. Application of GABA to acutely isolated human temporal cortical neurons elicited a large current with an average reversal potential of -65 mV, presumably mediated through a GABAA-activated chloride conductance. Application of varying concentrations of GABA generated a concentration/response relationship that could be well-fitted by a conventional sigmoidal curve, with an EC50 of 25.5 microM and a Hill coefficient of 1.0 4. Coapplication of the benzodiazepine clonazepam and 10 microM GABA augmented the amplitude of the GABA response. The concentration dependence of this benzodiazepine augmentation could be best-fitted by an equation assuming that the benzodiazepine interacted with two distinct binding sites, with differing potencies. The high-potency site had an EC50 of 0.06 nM and maximally contributed 38.5% augmentation to the total effect of clonazepam. The lower potency site had an EC50 of 16.4 nM, and contributed 66.1% maximal augmentation to the overall effect of clonazepam. These data derived from adult human temporal cortical neurons were very similar to our findings in adult rat sensory cortical neurons. 5. The effects of equimolar concentrations (100 nM) of clonazepam, a BZ1 and BZ2 agonist, and zolpidem, a selective BZ1 agonist, on acutely isolated human temporal cortical neurons were also investigated. Zolpidem and clonazepam were equally effective (71.5 vs. 65.0%, respectively) in potentiating GABA responses elicited by application of 10 microM GABA. This suggests that many of the functional benzodiazepine receptors in these neurons were of the BZ1 variety. 6. GABAergic synaptic inhibition was also studied with the use of patch-clamp recordings in slices of human temporal cortex. Extracellular stimulation at the white matter/gray matter border elicited compound synaptic events in layer II-V cortical neurons. These events usually consisted of an early excitatory postsynaptic potential (EPSP) and a late multiphasic inhibitory postsynaptic potential (IPSP). Application of either clonazepam or zolpidem (both at 100 nM) to the slice during extracellular stimulation reversibly augmented the late compound IPSP. 7. Spontaneous IPSPs were also recorded in approximately 50% of human temporal cortical neurons. These events did not have a preceding EPSP and were usually monopolar, with a single exponential rise and decay. This supported the idea that these events were triggered by spontaneous activity of GABAergic interneurons. Bath application of either clonazepam or zolpidem (both at 100nM) to the slice during ongoing spontaneous IPSP activity increased the amplitude and lengthened the time constant of decay of these events. 8. To our knowledge, this is one of the first detailed characterizations of the functional properties of GABAA-mediated inhibition in human cortical neurons using patch-clamp recordings in both isolated cells and slices of resected temporal cortex. Isolated pyramidal neurons exhibited GABAA-mediated currents that were comparable in many aspects with GABA currents recorded from adult rat cortical neurons, including similar GABA concentration/response curves, and similar two differing potency site effects for clonazepam augmentation of GABA currents. In addition, evoked and spontaneous IPSPs recorded in human cortical neurons appeared similar to IPSPs in rat cortical

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