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

2005 ◽  
Vol 94 (6) ◽  
pp. 3872-3883 ◽  
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.

scholarly journals Local Glutamate-Mediated Dendritic Plateau Potentials Change the State of the Cortical Pyramidal Neuron

2019 ◽  
Author(s):  
Peng P. Gao ◽  
Joseph. W. Graham ◽  
Wen-Liang Zhou ◽  
Jinyoung Jang ◽  
Sergio Angulo ◽  
...  
Keyword(s):  
Cell Body ◽  
Cortical Neurons ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Basal Dendrite ◽  
Plateau Potentials ◽  
Prepared State ◽  
Cortical Pyramidal Neurons ◽  
Afferent Inputs

AbstractDendritic spikes in thin dendritic branches (basal and oblique dendrites) of pyramidal neurons are traditionally inferred from spikelets measured in the cell body. Here, we used laser-spot voltage-sensitive dye imaging in cortical pyramidal neurons (rat brain slices) to investigate the voltage waveforms of dendritic potentials occurring in response to spatially-restricted glutamatergic inputs. Local dendritic potentials lasted 200–500 ms and propagated to the cell body where they caused sustained 10-20 mV depolarizations. Plateau potentials propagating from dendrite to soma, and action potentials propagating from soma to dendrite, created complex voltage waveforms in the middle of the thin basal dendrite, comprised of local sodium spikelets, local plateau potentials, and back-propagating action potentials, superimposed on each other. Our model replicated these experimental observations and made predictions, which were tested in experiments. Dendritic plateau potentials occurring in basal and oblique branches put pyramidal neurons into an activated neuronal state (“prepared state”), characterized by depolarized membrane potential and faster membrane responses. The prepared state provides a time window of 200-500 ms during which cortical neurons are particularly excitable and capable of following afferent inputs. At the network level, this predicts that sets of cells with simultaneous plateaus would provide cellular substrate for the formation of functional neuronal ensembles.New & NoteworthyIn cortical pyramidal neurons, we recorded glutamate-mediated dendritic plateau potentials using voltage imaging, and created a computer model that recreated experimental measures from dendrite and cell body. Our model made new predictions, which were then tested in experiments. Plateau potentials profoundly change neuronal state -- a plateau potential triggered in one basal dendrite depolarizes the soma and shortens membrane time constant, making the cell more susceptible to firing triggered by other afferent inputs.

scholarly journals Subunit-Specific Effects of Isoflurane on Neuronal Ih in HCN1 Knockout Mice

2009 ◽  
Vol 101 (1) ◽  
pp. 129-140 ◽  
Author(s):  
Xiangdong Chen ◽  
Shaofang Shu ◽  
Dylan P. Kennedy ◽  
Sarah C. Willcox ◽  
Douglas A. Bayliss
Keyword(s):  
Knockout Mice ◽  
Cortical Neurons ◽  
Current Amplitude ◽  
Membrane Properties ◽  
Neuronal Membrane ◽  
Hcn Channels ◽  
Wild Type ◽  
General Anesthetic ◽  
Cationic Current ◽  
Knockout Animals

The ionic mechanisms that contribute to general anesthetic actions have not been elucidated, although increasing evidence has pointed to roles for subthreshold ion channels, such as the HCN channels underlying the neuronal hyperpolarization-activated cationic current ( Ih). Here, we used conventional HCN1 knockout mice to test directly the contributions of specific HCN subunits to effects of isoflurane, an inhalational anesthetic, on membrane and integrative properties of motor and cortical pyramidal neurons in vitro. Compared with wild-type mice, residual Ih from knockout animals was smaller in amplitude and presented with HCN2-like properties. Inhibition of Ih by isoflurane previously attributed to HCN1 subunit-containing channels (i.e., a hyperpolarizing shift in half-activation voltage [ V1/2]) was absent in neurons from HCN1 knockout animals; the remaining inhibition of current amplitude could be attributed to effects on residual HCN2 channels. We also found that isoflurane increased temporal summation of excitatory postsynaptic potentials (EPSPs) in cortical neurons from wild-type mice; this effect was predicted by simulation of anesthetic-induced dendritic Ih inhibition, which also revealed more prominent summation accompanying shifts in V1/2 (an HCN1-like effect) than decreased current amplitude (an HCN2-like effect). Accordingly, anesthetic-induced EPSP summation was not observed in cortical cells from HCN1 knockout mice. In wild-type mice, the enhanced synaptic summation observed with low concentrations of isoflurane contributed to a net increase in cortical neuron excitability. In summary, HCN channel subunits account for distinct anesthetic effects on neuronal membrane properties and synaptic integration; inhibition of HCN1 in cortical neurons may contribute to the synaptically mediated slow-wave cortical synchronization that accompanies anesthetic-induced hypnosis.

scholarly journals Implantable microcoils for intracortical magnetic stimulation

2016 ◽  
Vol 2 (12) ◽  
pp. e1600889 ◽  
Author(s):  
Seung Woo Lee ◽  
Florian Fallegger ◽  
Bernard D. F. Casse ◽  
Shelley I. Fried
Keyword(s):  
Cortical Neurons ◽  
Magnetic Stimulation ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Behavioral Responses ◽  
Wide Range ◽  
Cortical Pyramidal Neurons ◽  
Over Time

Neural prostheses that stimulate the neocortex have the potential to treat a wide range of neurological disorders. However, the efficacy of electrode-based implants remains limited, with persistent challenges that include an inability to create precise patterns of neural activity as well as difficulties in maintaining response consistency over time. These problems arise from fundamental limitations of electrodes as well as their susceptibility to implantation and have proven difficult to overcome. Magnetic stimulation can address many of these limitations, but coils small enough to be implanted into the cortex were not thought strong enough to activate neurons. We describe a new microcoil design and demonstrate its effectiveness for both activating cortical neurons and driving behavioral responses. The stimulation of cortical pyramidal neurons in brain slices in vitro was reliable and could be confined to spatially narrow regions (<60 μm). The spatially asymmetric fields arising from the coil helped to avoid the simultaneous activation of passing axons. In vivo implantation was safe and resulted in consistent and predictable behavioral responses. The high permeability of magnetic fields to biological substances may yield another important advantage because it suggests that encapsulation and other adverse effects of implantation will not diminish coil performance over time, as happens to electrodes. These findings suggest that a coil-based implant might be a useful alternative to existing electrode-based devices. The enhanced selectivity of microcoil-based magnetic stimulation will be especially useful for visual prostheses as well as for many brain-computer interface applications that require precise activation of the cortex.

Prolonged Synaptic Integration in Perirhinal Cortical Neurons

2000 ◽  
Vol 83 (6) ◽  
pp. 3294-3298 ◽  
Author(s):  
John M. Beggs ◽  
James R. Moyer ◽  
John P. McGann ◽  
Thomas H. Brown
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Perirhinal Cortex ◽  
Visually Guided ◽  
Time Intervals ◽  
Current Step ◽  
Long Time ◽  
Temporal Learning ◽  
Whole Cell Recordings

Layer II/III of rat perirhinal cortex (PR) contains numerous late-spiking (LS) pyramidal neurons. When injected with a depolarizing current step, these LS cells typically delay spiking for one or more seconds from the onset of the current step and then sustain firing for the duration of the step. This pattern of delayed and sustained firing suggested a specific computational role for LS cells in temporal learning. This hypothesis predicts and requires that some layer II/III neurons should also exhibit delayed and sustained spiking in response to a train of excitatory synaptic inputs. Here we tested this prediction using visually guided, whole cell recordings from rat PR brain slices. Most LS cells (19 of 26) exhibited delayed spiking to synaptic stimulation (>1 s latency from the train onset), and the majority of these cells (13 of 19) also showed sustained firing that persisted for the duration of the synaptic train (5–10 s duration). Delayed and sustained firing in response to long synaptic trains has not been previously reported in vertebrate neurons. The data are consistent with our model that a circuit containing late spiking neurons can be used for encoding long time intervals during associative learning.

scholarly journals Mechanisms underlying serotonergic excitation of callosal projection neurons

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.

scholarly journals Single Cortical Neurons as Deep Artificial Neural Networks

2019 ◽  
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.

scholarly journals Voltage-gated sodium channels in neocortical pyramidal neurons display Cole-Moore activation kinetics

2017 ◽  
Author(s):  
Mara Almog ◽  
Tal Barkai ◽  
Angelika Lampert ◽  
Alon Korngreen
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Mechanism ◽  
Cortical Pyramidal Neurons

AbstractExploring the properties of action potentials is a crucial step towards a better understanding of the computational properties of single neurons and neural networks. The voltage-gated sodium channel is a key player in action potential generation. A comprehensive grasp of the gating mechanism of this channel can shed light on the biophysics of action potential generation. Most models of voltage-gated sodium channels assume it obeys a concerted Hodgkin and Huxley kinetic gating scheme. Here we performed high resolution voltage-clamp experiments from nucleated patches extracted from the soma of layer 5 (L5) cortical pyramidal neurons in rat brain slices. We show that the gating mechanism does not follow traditional Hodgkin and Huxley kinetics and that much of the channel voltage-dependence is probably due to rapid closed-closed transitions that lead to substantial onset latency reminiscent of the Cole-Moore effect observed in voltage-gated potassium conductances. This may have key implications for the role of sodium channels in synaptic integration and action potential generation.

scholarly journals Excitatory GABA in Rodent Developing Neocortex In Vitro

2008 ◽  
Vol 100 (2) ◽  
pp. 609-619 ◽  
Author(s):  
Sylvain Rheims ◽  
Marat Minlebaev ◽  
Anton Ivanov ◽  
Alfonso Represa ◽  
Rustem Khazipov ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Oscillatory Activity ◽  
Resting Membrane Potential ◽  
Network Oscillations ◽  
Excitatory Gaba

GABA depolarizes immature cortical neurons. However, whether GABA excites immature neocortical neurons and drives network oscillations as in other brain structures remains controversial. Excitatory actions of GABA depend on three fundamental parameters: the resting membrane potential ( Em), reversal potential of GABA ( EGABA), and threshold of action potential generation ( Vthr). We have shown recently that conventional invasive recording techniques provide an erroneous estimation of these parameters in immature neurons. In this study, we used noninvasive single N-methyl-d-aspartate and GABA channel recordings in rodent brain slices to measure both Em and EGABA in the same neuron. We show that GABA strongly depolarizes pyramidal neurons and interneurons in both deep and superficial layers of the immature neocortex (P2–P10). However, GABA generates action potentials in layer 5/6 (L5/6) but not L2/3 pyramidal cells, since L5/6 pyramidal cells have more depolarized resting potentials and more hyperpolarized Vthr. The excitatory GABA transiently drives oscillations generated by L5/6 pyramidal cells and interneurons during development (P5–P12). The NKCC1 co-transporter antagonist bumetanide strongly reduces [Cl−]i, GABA-induced depolarization, and network oscillations, confirming the importance of GABA signaling. Thus a strong GABA excitatory drive coupled with high intrinsic excitability of L5/6 pyramidal neurons and interneurons provide a powerful mechanism of synapse-driven oscillatory activity in the rodent neocortex in vitro. In the companion paper, we show that the excitatory GABA drives layer-specific seizures in the immature neocortex.

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