Semaphorin3F Drives Dendritic Spine Pruning through Rho-GTPase Signaling

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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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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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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Decreased numbers of dendritic spines on cortical pyramidal neurons in human chronic alcoholism

Neuroscience Letters ◽

10.1016/0304-3940(86)90425-8 ◽

1986 ◽

Vol 69 (1) ◽

pp. 115-119 ◽

Cited By ~ 50

Author(s):

Isidro Ferrer ◽

Isidro Fábregues ◽

Julia Rairiz ◽

Elena Galofré

Keyword(s):

Dendritic Spines ◽

Pyramidal Neurons ◽

Chronic Alcoholism ◽

Cortical Pyramidal Neurons

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Mechanisms underlying serotonergic excitation of callosal projection neurons

10.1101/197624 ◽

2017 ◽

Author(s):

Emily K. Stephens ◽

Arielle L. Baker ◽

Allan T. Gulledge

Keyword(s):

Intracellular Calcium ◽

Cortical Neurons ◽

Pyramidal Neurons ◽

Projection Neurons ◽

Calcium Dependent ◽

M Current ◽

Cation Conductance ◽

Cortical Pyramidal Neurons ◽

Excitatory Responses ◽

Callosal Projection

AbstractSerotonin (5-HT) selectively excites subpopulations of pyramidal neurons in the neocortex via activation of 5-HT2A (2A) receptors coupled to Gq subtype G-protein alpha subunits. Gq-mediated excitatory responses have been attributed primarily to suppression of potassium conductances, including those mediated by KV7 potassium channels (i.e., the M-current), or activation of nonspecific cation conductances that underly calcium-dependent afterdepolarizations (ADPs). However, 2A-dependent excitation of cortical neurons has not been extensively studied, and no consensus exists regarding the underlying ionic effector(s) involved. We tested potential mechanisms of serotonergic excitation in commissural/callosal projection neurons (COM neurons) in layer 5 of the mouse medial prefrontal cortex, a subpopulation of cortical pyramidal neurons that exhibit 2A-dependent excitation in response to 5-HT. In baseline conditions, 5-HT enhanced the rate of action potential generation in COM neurons experiencing suprathreshold somatic current injection. This serotonergic excitation was occluded by activation of muscarinic acetylcholine (ACh) receptors, confirming that 5-HT acts via the same Gq-signaling cascades engaged by ACh. Like ACh, 5-HT promoted the generation of calcium-dependent ADPs following spike trains. However, calcium was not necessary for serotonergic excitation, as responses to 5-HT were enhanced (by >100%), rather than reduced, by chelation of intracellular calcium with 10 mM BAPTA. This suggests intracellular calcium negatively regulates additional ionic conductances contributing to 2A excitation. Removal of extracellular calcium had no effect when intracellular calcium signaling was intact, but suppressed 5-HT response amplitudes, by about 50% (i.e., back to normal baseline values) when BAPTA was included in patch pipettes. This suggests that 2A excitation involves activation of a nonspecific cation conductance that is both calcium-sensitive and calcium-permeable. M-current suppression was found to be a third ionic effector, as blockade of KV7 channels with XE991 (10 μM) reduced serotonergic excitation by ∼50% in control conditions, and by ∼30% with intracellular BAPTA present. These findings demonstrate a role for at least three distinct ionic effectors, including KV7 channels, a calcium-sensitive and calcium-permeable nonspecific cation conductance, and the calcium-dependent ADP conductance, in mediating serotonergic excitation of COM neurons.

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Single Cortical Neurons as Deep Artificial Neural Networks

10.1101/613141 ◽

2019 ◽

Cited By ~ 4

Author(s):

David Beniaguev ◽

Idan Segev ◽

Michael London

Keyword(s):

Neural Networks ◽

Cortical Neurons ◽

Deep Neural Networks ◽

Pyramidal Neurons ◽

Classical Architecture ◽

Novel Approach ◽

Cortical Pyramidal Neurons ◽

Spatio Temporal ◽

Cortical Pyramidal Cell

AbstractWe introduce a novel approach to study neurons as sophisticated I/O information processing units by utilizing recent advances in the field of machine learning. We trained deep neural networks (DNNs) to mimic the I/O behavior of a detailed nonlinear model of a layer 5 cortical pyramidal cell, receiving rich spatio-temporal patterns of input synapse activations. A Temporally Convolutional DNN (TCN) with seven layers was required to accurately, and very efficiently, capture the I/O of this neuron at the millisecond resolution. This complexity primarily arises from local NMDA-based nonlinear dendritic conductances. The weight matrices of the DNN provide new insights into the I/O function of cortical pyramidal neurons, and the approach presented can provide a systematic characterization of the functional complexity of different neuron types. Our results demonstrate that cortical neurons can be conceptualized as multi-layered “deep” processing units, implying that the cortical networks they form have a non-classical architecture and are potentially more computationally powerful than previously assumed.

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Suppression of Ih Contributes to Propofol-Induced Inhibition of Mouse Cortical Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.00389.2005 ◽

2005 ◽

Vol 94 (6) ◽

pp. 3872-3883 ◽

Cited By ~ 36

Author(s):

Xiangdong Chen ◽

Shaofang Shu ◽

Douglas A. Bayliss

Keyword(s):

Cortical Neurons ◽

Pyramidal Neurons ◽

Brain Slices ◽

Current Amplitude ◽

Hcn Channels ◽

General Anesthetic ◽

Large Shift ◽

Fast Kinetics ◽

Membrane Hyperpolarization ◽

Cortical Pyramidal Neurons

The contributions of the hyperpolarization-activated current, Ih, to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native Ih in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal Ih currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating Ih in cortical neurons at a clinically relevant concentration (5 μM); inhibition of Ih involved a hyperpolarizing shift in half-activation voltage (Δ V1/2 approximately −9 mV) and a decrease in maximal available current (∼36% inhibition, measured at −120 mV). With the slower form of Ih expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 μM propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1–HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABAA and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the Ih blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate Ih in cortical pyramidal neurons—and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells.

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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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