Altered dendritic complexity affects firing properties of cortical layer 2/3 pyramidal neurons in mice lacking the 5-HT3A receptor

We have previously shown that the serotonergic input on Cajal-Retzius cells, mediated by 5-HT3 receptors, plays an important role in the early postnatal maturation of the apical dendritic trees of layer 2/3 pyramidal neurons. We reported that knockout mice lacking the 5-HT3A receptor showed exuberant apical dendrites of these cortical pyramidal neurons. Because model studies have shown the role of dendritic morphology on neuronal firing pattern, we used the 5-HT3A knockout mouse to explore the impact of dendritic hypercomplexity on the electrophysiological properties of this specific class of neurons. Our experimental results show that hypercomplexity of the apical dendritic tuft of layer 2/3 pyramidal neurons affects neuronal excitability by reducing the amount of spike frequency adaptation. This difference in firing pattern, related to a higher dendritic complexity, was accompanied by an altered development of the afterhyperpolarization slope with successive action potentials. Our abstract and realistic neuronal models, which allowed manipulation of the dendritic complexity, showed similar effects on neuronal excitability and confirmed the impact of apical dendritic complexity. Alterations of dendritic complexity, as observed in several pathological conditions such as neurodegenerative diseases or neurodevelopmental disorders, may thus not only affect the input to layer 2/3 pyramidal neurons but also shape their firing pattern and consequently alter the information processing in the cortex.

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Response Properties and Synchronization of Rhythmically Firing Dendritic Neurons

Journal of Neurophysiology ◽

10.1152/jn.00810.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 208-219 ◽

Cited By ~ 45

Author(s):

Joshua A. Goldberg ◽

Chris A. Deister ◽

Charles J. Wilson

Keyword(s):

Pyramidal Neurons ◽

Phase Response Curve ◽

Qualitative Difference ◽

Apical Dendrite ◽

Neuronal Firing ◽

Closed Form Expression ◽

Pass Filter ◽

Cortical Pyramidal Neurons ◽

The Impact ◽

High Pass

The responsiveness of rhythmically firing neurons to synaptic inputs is characterized by their phase-response curve (PRC), which relates how weak somatic perturbations affect the timing of the next action potential. The shape of the somatic PRC is an important determinant of collective network dynamics. Here we study theoretically and experimentally the impact of distally located synapses and dendritic nonlinearities on the synchronization properties of rhythmically firing neurons. By combining the theories of quasi-active cables and phase-coupled oscillators we derive an approximation for the dendritic responsiveness, captured by the neuron's dendritic PRC (dPRC). This closed-form expression indicates that the dPRCs are linearly filtered versions of the somatic PRC and that the filter characteristics are determined by the passive and active properties of the dendrite. The passive properties induce leftward shifts in the dPRCs and attenuate them. Our analysis yields a single dimensionless parameter that classifies active dendritic conductances as either regenerative conductances that counter the passive properties by boosting the dPRCs or restorative conductances that high-pass filter the dPRCs. Thus dendritic properties can generate a qualitative difference between the somatic and dendritic PRCs. As a result collective dynamics can be qualitatively different depending on the location of the synapse, the neuronal firing rates, and the dendritic nonlinearities. Finally, we use dual whole cell recordings from the soma and apical dendrite of cortical pyramidal neurons to test these predictions and find that empirical dPRCs are shifted leftward, as predicted, but may also display high-pass characteristics resulting from the restorative dendritic HCN (h) current.

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Pre- and Postsynaptic Activation of M-Channels By a Novel Opener Dampens Neuronal Firing and Transmitter Release

Journal of Neurophysiology ◽

10.1152/jn.00634.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 283-295 ◽

Cited By ~ 48

Author(s):

Asher Peretz ◽

Anton Sheinin ◽

Cuiyong Yue ◽

Nurit Degani-Katzav ◽

Gilad Gibor ◽

...

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Critical Role ◽

Hippocampal Slices ◽

Gaba Release ◽

Neuronal Firing ◽

Dorsal Root Ganglion Neurons ◽

Postsynaptic Currents ◽

M Channels ◽

Ganglion Neurons

The M-type K+ current (M-current), encoded by Kv7.2/3 (KCNQ2/3) K+ channels, plays a critical role in regulating neuronal excitability because it counteracts subthreshold depolarizations. Here we have characterized the functions of pre- and postsynaptic M-channels using a novel Kv7.2/3 channel opener, NH6, which we synthesized as a new derivative of N-phenylanthranilic acid. NH6 exhibits a good selectivity as it does not affect Kv7.1 and IKS K+ currents as well as NR1/NR2B, AMPA, and GABAA receptor-mediated currents. Superfusion of NH6 increased recombinant Kv7.2/3 current amplitude (EC50 = 18 μM) by causing a hyperpolarizing shift of the voltage activation curve and by markedly slowing the deactivation kinetics. Activation of native M-currents by NH6 robustly reduced the number of evoked and spontaneous action potentials in cultured cortical, hippocampal and dorsal root ganglion neurons. In hippocampal slices, NH6 decreased somatically evoked spike afterdepolarization of CA1 pyramidal neurons and induced regular firing in bursting neurons. Activation of M-channels by NH6, potently reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents. Activation of M-channels also decreased the frequency of miniature excitatory (mEPSC) and inhibitory (mIPSC) postsynaptic currents without affecting their amplitude and waveform, thus suggesting that M-channels presynaptically inhibit glutamate and GABA release. Our results suggest a role of presynaptic M-channels in the release of glutamate and GABA. They also indicate that M-channels act pre- and postsynaptically to dampen neuronal excitability.

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Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

Journal of Neurophysiology ◽

10.1152/jn.00524.2012 ◽

2012 ◽

Vol 108 (10) ◽

pp. 2810-2818 ◽

Cited By ~ 13

Author(s):

Jean-Didier Breton ◽

Greg J. Stuart

Keyword(s):

Potassium Channels ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Barrel Cortex ◽

Receptor Activation ◽

Gabab Receptors ◽

Membrane Properties ◽

Dendritic Excitability ◽

The Impact ◽

Neuronal Output

GABAB receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABAB receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABAB receptors. Here, we investigate the impact of GABAB receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABAB receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 μM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABAB receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABAB receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABAB receptors regulated neuronal output in different ways. Activation of somatic GABAB receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABAB receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABAB receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABAB receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABAB receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

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A Simulation Study Investigating the Impact of Dendritic Morphology and Synaptic Topology on Neuronal Firing Patterns

Neural Computation ◽

10.1162/neco.2009.11-08-913 ◽

2010 ◽

Vol 22 (4) ◽

pp. 1086-1111 ◽

Cited By ~ 5

Author(s):

Jen-Yung Chen

Keyword(s):

Information Processing ◽

Computational Models ◽

Dendritic Morphology ◽

Neuronal Firing ◽

Membrane Properties ◽

Neuron Models ◽

Spatial And Temporal Scales ◽

Brain Functions ◽

Scaling Analyses ◽

The Impact

In the brain, complex information interactions among neurons span several spatial and temporal scales, making it extremely difficult to identify the principles governing neural information processing. In this study, we used computational models to investigate the impact of dendritic morphology and synaptic topology on patterns of neuronal firing. We first constructed Hodgkin-Huxley-type neuron models that possessed dendrites with different morphological features. We then simulated the responses of these neurons to a number of spatiotemporal input patterns. The similarity between neuronal responses to different patterned inputs was effectively evaluated by a novel combination of metric space analysis and multidimensional scaling analyses. The results showed that neurons with different morphological or anatomical features exhibit differences in stimulus-specific temporal encoding and firing reliability. These findings support the idea that in addition to biophysical membrane properties, the dendritic morphology and the synaptic topology of a neuron can play a significant role in neuronal information processing and may directly contribute to various brain functions.

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Impact of inhibitory constraint of interneurons on neuronal excitability

Journal of Neurophysiology ◽

10.1152/jn.00047.2013 ◽

2013 ◽

Vol 110 (11) ◽

pp. 2520-2535 ◽

Cited By ~ 25

Author(s):

Vallent Lee ◽

Jamie Maguire

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Molecular Layer ◽

Critical Role ◽

Tonic Inhibition ◽

Stratum Radiatum ◽

Gabaergic Inhibition ◽

Seizure Susceptibility ◽

Ca1 Pyramidal Neurons ◽

The Impact

Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice ( Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre−/− littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre−/− controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

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P38 Regulates Kainic Acid-Induced Seizure and Neuronal Firing via Kv4.2 Phosphorylation

International Journal of Molecular Sciences ◽

10.3390/ijms21165921 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5921

Author(s):

Jia-hua Hu ◽

Cole Malloy ◽

Dax A. Hoffman

Keyword(s):

Kainic Acid ◽

Molecular Mechanisms ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Neuronal Firing ◽

Dependent Manner ◽

Membrane Excitability ◽

Hippocampal Pyramidal Neurons ◽

K Current

The subthreshold, transient A-type K+ current is a vital regulator of the excitability of neurons throughout the brain. In mammalian hippocampal pyramidal neurons, this current is carried primarily by ion channels comprising Kv4.2 α-subunits. These channels occupy the somatodendritic domains of these principle excitatory neurons and thus regulate membrane voltage relevant to the input–output efficacy of these cells. Owing to their robust control of membrane excitability and ubiquitous expression in the hippocampus, their dysfunction can alter network stability in a manner that manifests in recurrent seizures. Indeed, growing evidence implicates these channels in intractable epilepsies of the temporal lobe, which underscores the importance of determining the molecular mechanisms underlying their regulation and contribution to pathologies. Here, we describe the role of p38 kinase phosphorylation of a C-terminal motif in Kv4.2 in modulating hippocampal neuronal excitability and behavioral seizure strength. Using a combination of biochemical, single-cell electrophysiology, and in vivo seizure techniques, we show that kainic acid-induced seizure induces p38-mediated phosphorylation of Thr607 in Kv4.2 in a time-dependent manner. The pharmacological and genetic disruption of this process reduces neuronal excitability and dampens seizure intensity, illuminating a cellular cascade that may be targeted for therapeutic intervention to mitigate seizure intensity and progression.

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The effect of single pyramidal neuron firing across and within layers in mouse V1

10.1101/232603 ◽

2017 ◽

Author(s):

Jochen Meyer ◽

Peyman Golshani ◽

Stelios M. Smirnakis

Keyword(s):

Patch Clamp ◽

Single Cell ◽

Pyramidal Cell ◽

Pyramidal Neurons ◽

Population Activity ◽

Cell Stimulation ◽

Layer 2 ◽

Layer 4 ◽

Aggregate Population ◽

The Impact

AbstractThe influence of cortical cell spiking activity on nearby cells has been studied extensively in vitro. Less is known, however, about the impact of single cell firing on local cortical networks in vivo. In a pioneering study, Kwan et al. (Kwan et al., 2012) reported that in mouse layer 2/3 (L2/3), under anesthesia, stimulating a single pyramidal cell recruits ~1.7% of neighboring pyramidal units. Here we employ two-photon calcium imaging, in conjunction with single-cell patch clamp stimulation, to probe, in both the awake and lightly anesthetized states, how i) activating single L2/3 pyramidal neurons recruits neighboring units within L2/3 and from layer 4 (L4) to L2/3, and whether ii) activating single pyramidal neurons changes population activity in local circuit. To do this, it was essential to develop an algorithm capable of quantifying how sensitive the calcium signal is at detecting effectively recruited units (“followers”). This algorithm allowed us to estimate the chance of detecting a follower as a function of the probability that an epoch of stimulation elicits one extra action potential (AP) in the follower cell. Using this approach, we found only a small fraction (<0.75%) of L2/3 cells to be significantly activated within a radius of ~200 μm from a stimulated neighboring L2/3 pyramidal cell. This fraction did not change significantly in the awake versus the lightly anesthetized state, nor when stimulating L2/3 versus underlying L4 pyramidal neurons. These numbers are in general agreement with, though lower than, the percentage of neighboring cells (2.1%) reported by Kwan et al. to be activated upon stimulating single L2/3 pyramidal neurons under anesthesia (Kwan et al., 2012). Interestingly, despite the small number of individual units found to be reliably driven, we did observe a modest but significant elevation in aggregate population responses compared to sham stimulation. This underscores the distributed impact that single cell stimulation has on neighboring microcircuit responses, revealing only a small minority of relatively strongly connected partners.One Sentence SummaryPatch-clamp stimulation in conjunction with 2-photon imaging shows that activating single layer-2/3 or layer-4 pyramidal neurons produces few (<1% of local units) reliable singlecell followers in L2/3 of mouse area V1, either under light anesthesia or in quiet wakefulness: instead, single cell stimulation was found to elevate aggregate population activity in a weak but highly distributed fashion.

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Potassium channels contribute to activity-dependent scaling of dendritic inhibition

10.1101/098889 ◽

2017 ◽

Author(s):

Jeremy T. Chang ◽

Michael J. Higley

Keyword(s):

Potassium Channels ◽

Neuronal Activity ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Critical Role ◽

Pyramidal Cells ◽

Gabaergic Inhibition ◽

Voltage Gated ◽

The Impact ◽

Activity Dependent

AbstractGABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.Significance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

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H-Channels and Seizures: Less is More

Epilepsy Currents ◽

10.1111/j.1535-7511.2005.05302.x ◽

2005 ◽

Vol 5 (3) ◽

pp. 89-90 ◽

Cited By ~ 1

Author(s):

Nicholas P. Poolos

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Cortical Layer ◽

Neuronal Firing ◽

Less Is More ◽

Electrographic Seizures ◽

Seizure Episode ◽

H Channels

Seizure-induced Plasticity of h Channels in Entorhinal Cortical Layer III Pyramidal Neurons Shah MM, Anderson AE, Leung V, Lin X, Johnston D Neuron 2004;44:495–508 The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurons in chronic epilepsy. Discerning the mechanisms underlying signal integration within EC neurons is essential for understanding network excitability alterations involving the hippocampus during epilepsy. Twenty-four hours after a single seizure episode when no behavioral or electrographic seizures occurred, we found enhanced spontaneous activity still present in the rat EC in vivo and in vitro. The increased excitability was accompanied by a profound reduction in Ih in EC layer III neurons and a significant decline in hyperpolarization-activated cation (HCN)1 and HCN2 subunits that encode for h channels. Consequently, dendritic excitability was enhanced, resulting in increased neuronal firing despite hyperpolarized membrane potentials. The loss of Ih and the increased neuronal excitability persisted for 1 week after seizures. Our results suggest that dendritic Ih plays an important role in determining the excitability of EC layer III neurons and their associated neural networks.

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Opening of KATP Channel Regulates Tonic Currents From Pyramidal Neurons in Rat Brain

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2016.455 ◽

2017 ◽

Vol 44 (6) ◽

pp. 718-725

Author(s):

Zhongxia Li ◽

Jiangping Wang ◽

Huimin Yu ◽

Kewen Jiang

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

Cortical Layer ◽

Gaba A ◽

Gaba Inhibition ◽

Ambient Gaba ◽

Neuronal Functions ◽

Tonic Current ◽

The Impact

AbstractBackground: ATP-sensitive K+ (KATP) channels couple metabolic state to cellular excitability. Activation of neuronal and astrocytic mitochondrial KATP (mitoKATP) channels regulates a variety of neuronal functions. However, less is known about the impact of mitoKATP on tonic γ-aminobutyric acid (GABA) inhibition. Tonic GABA inhibition is mediated by the binding of ambient GABA on extrasynaptic GABA A-type receptors (GABAARs) and is involved in regulating neuronal excitability. Methods: We determined the impact of activation of KATP channels with diazoxide (DIZ) on tonic inhibition and recorded tonic current from rat cortical layer 5 pyramidal cells by patch-clamp recordings. Results: We found that neonatal tonic current increased with an increase in GABA concentration, which was partially mediated by the GABA A-type receptor (GABAAR) α5, and likely the δ subunits. Activation of KATP channels resulted in decreased tonic current in newborns, but there was increased tonic current during the second postnatal week. Conclusions: These findings suggest that activation of KATP channels with DIZ regulates GABAergic transmission in neocortical pyramidal cells during development.

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