Dendritic Action Potentials Research Articles

Voltage‐gated potassium channels and the diversity of electrical signalling

Since Hodgkin and Huxley discovered the potassium current that underlies the falling phase of action potentials in the squid giant axon, the diversity of voltage-gated potassium (Kv) channels has been manifested in multiple ways. The large and extended potassium channel family is evolutionarily conserved molecularly and functionally. Alternative splicing and RNA editing of Kv channel genes diversify the channel property and expression level. The mix-and-match of subunits in a Kv channel that contains four similar or identical pore-forming subunits and additional auxiliary subunits further diversify Kv channels. Moreover, targeting of different Kv channels to specific subcellular compartments and local translation of Kv channel mRNA in neuronal processes diversify axonal and dendritic action potentials and influence how synaptic plasticity may be modulated. As one indication of the evolutionary conservation of Kv1 channel functions, mutations of the Shaker potassium channel gene in Drosophila and the KCNA1 gene for its mammalian orthologue, Kv1.1, cause hyperexcitability near axon branch points and nerve terminals, thereby leading to uncontrolled movements and recapitulating the episodic ataxia-1 (EA1) symptoms in human patients.

Voltage-gated Potassium Channels and the Diversity of Electrical Signaling

Abstract Since Hodgkin and Huxley discovered the potassium current that underlies the falling phase of action potentials in the squid giant axon, the diversity of voltage-gated potassium (Kv) channels has been manifested in multiple ways. The large and extended potassium channel family is evolutionarily conserved molecularly and functionally. Alternative splicing and RNA editing of Kv channel genes diversify the channel property and expression level. The mix-and-match of subunits in a Kv channel that contains four similar or identical pore-forming subunits and additional auxiliary subunits further diversify Kv channels. Moreover, targeting of different Kv channels to specific subcellular compartments and local translation of Kv channel mRNA in neuronal processes diversify axonal and dendritic action potentials and influence how synaptic plasticity may be modulated. As one indication of the evolutionary conservation of Kv1 channel functions, mutations of the Shaker potassium channel gene in Drosophila and the KCNA1 gene for its mammalian orthologue, Kv1.1, cause hyperexcitability near axon branch points and nerve terminals, thereby leading to uncontrolled movements and recapitulating the episodic ataxia-1 (EA1) symptoms in human patients.

Initiation and Propagation of Action Potentials in Gonadotropin-Releasing Hormone Neuron Dendrites

Gonadotropin-releasing hormone (GnRH) neurons are the final output neurons in a complex neuronal network that regulates fertility. The morphology of GnRH neuron dendrites is very different to other central neurons in that they are very long, thin, and unbranched. To study the function of these dendrites, we have used Na(+) and Ca(2+) imaging in combination with dual soma and dendrite electrical recordings in brain slices from GnRH-GFP mice. Here, we show that GnRH neurons actively propagate Na(+) spikes throughout their dendrites. Multisite dendritic recordings confirmed that these spikes were observed in one of the dendrites before the soma in the great majority of neurons tested. Na(+) imaging experiments revealed that the initial 150 μm of dendrite has a higher density of functional Na(+) channels than more distal regions, suggesting that this region of dendrite is highly excitable and may be the site of spike initiation. Finally, we show that the depolarization from dendritic spikes opens voltage-gated Ca(2+) channels giving rise to dendritic Ca(2+) transients. Together, these findings suggest that the proximal dendrites of GnRH neurons are highly excitable and are likely to be the site of action potential initiation in these neurons.

Spatial Distributions of GABA Receptors and Local Inhibition of Ca2+ Transients Studied with GABA Uncaging in the Dendrites of CA1 Pyramidal Neurons

GABA(γ-amino-butylic acid)-mediated inhibition in the dendrites of CA1 pyramidal neurons was characterized by two-photon uncaging of a caged-GABA compound, BCMACM-GABA, and one-photon uncaging of RuBi-GABA in rat hippocampal slice preparations. Although we found that GABAA-mediated currents were diffusely distributed along the dendrites, currents elicited at the branch points of the apical dendritic trunk were approximately two times larger than those elsewhere in the dendrite. We examined the inhibitory action of the GABA-induced currents on Ca2+ transients evoked with a single back-propagating action potential (bAP) in oblique dendrites. We found that GABA uncaging selectively inhibited the Ca2+ transients in the region adjacent (<20 µm) to the uncaging site, and that GABA uncaging was effective only within a short period after bAP (<20 ms). The strength of inhibition was linearly related to the amplitudes of the GABA currents, suggesting that the currents inhibited a sustained, subthreshold after-depolarization without preventing propagation of bAP. GABA uncaging at the dendritic branch points inhibited Ca2+ transients farther into dendritic branches (>20 µm). Our data indicate that GABA inhibition results in spatially confined inhibition of Ca2+ transients shortly after bAP, and suggest that this effect is particularly potent at the dendritic branch points where GABA receptors cluster.

GABABReceptor Modulation of Voltage-Sensitive Calcium Channels in Spines and Dendrites

Although primarily studied at the cell body, GABA(B) receptors (GABA(B)Rs) are abundant at spines and dendrites of cortical pyramidal neurons, where they are positioned to influence both synaptic and dendritic function. Here, we examine how GABA(B)Rs modulate calcium (Ca) signals evoked by action potentials (APs) in spines and dendrites of layer 2/3 pyramidal neurons in mouse prefrontal cortex. We first use two-photon microscopy to show that GABA(B)Rs inhibit AP Ca signals throughout the entire dendritic arbor of these neurons. We then use local pharmacology and GABA uncaging to show that dendritic GABA(B)Rs also decrease the input resistance, shorten the AP afterdepolarization, and generate inhibitory postsynaptic potentials. However, we find that these electrophysiological effects recorded at the cell body do not correlate with the inhibition of AP Ca signals measured in spines and dendrites. Instead, we use voltage-clamp recordings to show that GABA(B)Rs directly inhibit several subtypes of voltage-sensitive calcium channels (VSCCs) in both spines and dendrites. Given the importance of VSCC-mediated Ca signals for neuronal function, our results have implications for the functional role of dendritic GABA(B)Rs in the prefrontal cortex and throughout the brain.

Optically measured propagation speed of action potential in dendrites during different regenerative events

Optically measured propagation speed of action potential in dendrites during different regenerative events

Second‐harmonic generation voltage imaging at subcellular resolution in rat hippocampal slices

Action potential (AP) is a major signaling mechanism in the neuronal networks. Dendritic AP propagation is important for information processing within the individual neurons. Due to limitations of electrode-based techniques most research on subcellular AP propagation has been restricted to soma and proximal parts of the primary dendrites. Development of voltage-sensitive dyes (VSD) has opened up a possibility to measure voltage changes in the oblique dendrites and the spines. Membrane-bound organic VSD can be used both for fluorescent imaging and imaging of second-harmonic generation (SHG). Both phenomena are voltage dependent and can be used for measuring membrane potential changes. However, changes in SHG are linear to the change in the local membrane potential and its slope is constant across different compartments of cells. Although SHG demonstrates reasonable change with membrane voltage (over 10% per 100 mV), the signal-to-noise (S/N) ratio is currently lower in SHG measurement than in fluorescent methods.

Rapid time course of action potentials in spines and remote dendrites of mouse visual cortex neurons

Axonally initiated action potentials back-propagate into spiny dendrites of central mammalian neurons and thereby regulate plasticity at excitatory synapses on individual spines as well as linear and supralinear integration of synaptic inputs along dendritic branches. Thus, the electrical behaviour of individual dendritic spines and terminal dendritic branches is critical for the integrative function of nerve cells. The actual dynamics of action potentials in spines and terminal branches, however, are not entirely clear, mostly because electrode recording from such small structures is not feasible. Additionally, the available membrane potential imaging techniques are limited in their sensitivity and require substantial signal averaging for the detection of electrical events at the spatial scale of individual spines. We made a critical improvement in the voltage-sensitive dye imaging technique to achieve multisite recordings of backpropagating action potentials from individual dendritic spines at a high frame rate. With this approach, we obtained direct evidence that in layer 5 pyramidal neurons from the visual cortex of juvenile mice, the rapid time course of somatic action potentials is preserved throughout all cellular compartments, including dendritic spines and terminal branches of basal and apical dendrites. The rapid time course of the action potential in spines may be a critical determinant for the precise regulation of spike timing-dependent synaptic plasticity within a narrow time window.

Loss of sensory input increases the intrinsic excitability of layer 5 pyramidal neurons in rat barrel cortex.

Development of the cortical map is experience dependent, with different critical periods in different cortical layers. Previous work in rodent barrel cortex indicates that sensory deprivation leads to changes in synaptic transmission and plasticity in layer 2/3 and 4. Here, we studied the impact of sensory deprivation on the intrinsic properties of layer 5 pyramidal neurons located in rat barrel cortex using simultaneous somatic and dendritic recording. Sensory deprivation was achieved by clipping all the whiskers on one side of the snout. Loss of sensory input did not change somatic active and resting membrane properties, and did not influence dendritic action potential (AP) backpropagation. In contrast, sensory deprivation led to an increase in the percentage of layer 5 pyramidal neurons showing burst firing. This was associated with a reduction in the threshold for generation of dendritic calcium spikes during high-frequency AP trains. Cell-attached recordings were used to assess changes in the properties and expression of dendritic HCN channels. These experiments indicated that sensory deprivation caused a decrease in HCN channel density in distal regions of the apical dendrite. To assess the contribution of HCN down-regulation on the observed increase in dendritic excitability following sensory deprivation, we investigated the impact of blocking HCN channels. Block of HCN channels removed differences in dendritic calcium electrogenesis between control and deprived neurons. In conclusion, these observations indicate that sensory loss leads to increased dendritic excitability of cortical layer 5 pyramidal neurons. Furthermore, they suggest that increased dendritic calcium electrogenesis following sensory deprivation is mediated in part via down-regulation of dendritic HCN channels.

SK channels gate information processing in vivo by regulating an intrinsic bursting mechanism seen in vitro.

Understanding the mechanistic substrates of neural computations that lead to behavior remains a fundamental problem in neuroscience. In particular, the contributions of intrinsic neural properties such as burst firing and dendritic morphology to the processing of behaviorally relevant sensory input have received much interest recently. Pyramidal cells within the electrosensory lateral line lobe of weakly electric fish display an intrinsic bursting mechanism that relies on somato-dendritic interactions when recorded in vitro: backpropagating somatic action potentials trigger dendritic action potentials that lead to a depolarizing afterpotential (DAP) at the soma. We recorded intracellularly from these neurons in vivo and found firing patterns that were quite different from those seen in vitro: we found no evidence for DAPs as each somatic action potential was followed by a pronounced afterhyperpolarization (AHP). Calcium chelators injected in vivo reduced the AHP, thereby unmasking the DAP and inducing in vitro-like bursting in pyramidal cells. These bursting dynamics significantly reduced the cell's ability to encode the detailed time course of sensory input. We performed additional in vivo pharmacological manipulations and mathematical modeling to show that calcium influx through N-methyl-d-aspartate (NMDA) receptors activate dendritic small conductance (SK) calcium-activated potassium channels, which causes an AHP that counteracts the DAP and leads to early termination of the burst. Our results show that ion channels located in dendrites can have a profound influence on the processing of sensory input by neurons in vivo through the modulation of an intrinsic bursting mechanism.

Multicompartment leaky integrate and fire neuron modeling with multiexponentials

Introduction Dendritic processing is paramount in the mammalian olfactory bulb where mitral cells modulate each other via granule cell interneurons that synapse on the mitral cells' lateral dendrites. This motivated us to construct computationally lean multicompartment leaky integrate and fire (LIF) neurons such that each compartment's membrane potential is described by six exponentials. This enables the model to avoid differential equations and calculate the membrane potential only upon receiving synaptic events and, like the LIF point neuron, employs simple rules for propagating and attenuating dendritic action potentials.

Robust short-term memory in the neuronal field model involving nonlinear dendritic integration

Several studies has suggested that a single dendritic branch can be a computational subunit which locally integrate the synaptic inputs to produce dendritic action potential (dAP) [1]. In the present study, we investigate the influence of dAPs on the network dynamics by using a neuronal two-field model incorporating the dendrite nonlinearly. We discuss functional significance of the unique dynamics present in our model.

Activity-Dependent Control of Neuronal Output by Local and Global Dendritic Spike Attenuation

Neurons possess elaborate dendritic arbors which receive and integrate excitatory synaptic signals. Individual dendritic subbranches exhibit local membrane potential supralinearities, termed dendritic spikes, which control transfer of local synaptic input to the soma. Here, we show that dendritic spikes in CA1 pyramidal cells are strongly regulated by specific types of prior input. While input in the linear range is without effect, supralinear input inhibits subsequent spikes, causing them to attenuate and ultimately fail due to dendritic Na(+) channel inactivation. This mechanism acts locally within the boundaries of the input branch. If an input is sufficiently strong to trigger axonal action potentials, their back-propagation into the dendritic tree causes a widespread global reduction in dendritic excitability which is prominent after firing patterns occurring in vivo. Together, these mechanisms control the capability of individual dendritic branches to trigger somatic action potential output. They are invoked at frequencies encountered during learning, and impose limits on the storage and retrieval rates of information encoded as branch excitability.

A tingle of extra excitement with voltage dependence of NMDA receptor activation

A tingle of extra excitement with voltage dependence of NMDA receptor activation

Regional distribution of calcium elevation during sensory transduction in spider mechanoreceptor neurons

Spider mechanosensory VS-3 neurons receive peripheral efferent synaptic modulation, with regional variations in the types of efferent synapses and transmitter receptors. VS-3 somata possess a voltage-activated calcium current, but the levels and time courses of calcium changes in other regions are unknown. The roles of calcium in these neurons are not completely understood, but could include modulation of both mechanosensitivity and response dynamics. Here, we measured calcium concentration rises caused by single, mechanically induced action potentials in VS-3 sensory dendrites, somata and axons, using Oregon Green BAPTA-1 fluorescence. Calcium concentration rose by ∼1 nM following each action potential. Time courses of calcium rise and fall were similar in the three regions but the rise in amplitude was about 50% higher in the sensory dendrite than in the soma. Antibody to the Ca V3.1(α 1g) isotype of T-type calcium channel labeled all three neuronal regions. Some Ca V3.1 labeling colocalized with synapsin labeling, suggesting that calcium channels play some part in efferent modulation. We conclude that mechanically stimulated action potentials start near sensory dendrite tips and pass rapidly through the neurons to the axons, activating low voltage activated calcium channels in all three regions and causing calcium concentration to rise rapidly in each region. These results suggest important roles for calcium in several stages of mechanosensation.

Increased bursting in layer 2/3 neurones of awake neocortex

Increased bursting in layer 2/3 neurones of awake neocortex

High frequency action potential bursts (≥ 100 Hz) in L2/3 and L5B thick tufted neurons in anaesthetized and awake rat primary somatosensory cortex

High frequency (>or= 100 Hz) bursts of action potentials (APs) generated by neocortical neurons are thought to increase information content and, through back-propagation, to influence synaptic integration and efficacy in distal dendritic compartments. It was recently shown in acute slice experiments that intrinsic bursting properties differ between neocortical L2/3 and L5B (thick tufted) neurons. In L2/3 neurons for instance, dendritic APs were brief and generated only one additional AP after the initial somatic AP. In L5B neurons, dendritic plateau potentials facilitated the generation of trains of three or more APs. We recently showed in vivo that spiking frequencies are very different for L2/3 and L5B thick tufted neurons under anaesthesia. Here, we addressed the question whether in vivo the bursting properties are different for these two cell types. We recorded from L2/3 and L5B thick tufted neurons of rat primary somatosensory (barrel) cortex under anaesthetized and awake conditions and found that AP activity is dominated by single APs. In addition, we found that in the anaesthetized animal also bursts of two APs were observed in L2/3 neurons but the relative occurrence of these bursts was low. In L5B thick tufted neurons, bursts consisting of up to six APs were recorded and their relative occurrence was significantly higher. Frequencies within bursts were also significantly higher in L5B thick tufted neurons than in L2/3 neurons. In awake (head-restrained) animals, average spike frequencies of L2/3 and L5B thick tufted neurons were surprisingly similar to spike rates under anaesthesia. However, bursting behaviour in L2/3 neurons was comparable to L5B thick tufted neurons. Thus, the distribution of interspike intervals was changed in L2/3 neurons without affecting the average spiking rate. We observed bursts consisting of up to five APs in both cell types and both probability of bursts and AP frequency within bursts were similar for L2/3 and L5B thick tufted neurons. Our analysis shows that most cortical APs occur as single APs, although a minor fraction of APs in L2/3 and L5B thick tufted neurons are part of high frequency bursts (15%). This AP bursting is dependent on the behavioural state of the animal in a cell-type dependent manner.

GABAergic control of dendritic calcium dynamics in striatal medium spiny neurons

Event Abstract Back to Event GABAergic control of dendritic calcium dynamics in striatal medium spiny neurons Johannes Hjorth1*, Patrik Krieger2, Rodrigo F. Oliveira3, Kim T. Blackwell3 and Jeanette H. Kotaleski1 1 Royal Institute of Technology , Sweden 2 Karolinska Institute, Sweden 3 Krasnow Institute, United States Introduction: Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites [1, 2, 3]. Increased calcium levels trigger changes in plasticity [4, 5], which is important for learning and other functions [6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites [7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of GABAergic inputs on the dendritic calcium dynamics is investigated. Model: A previously published MS model [8] was reimplemented in GENESIS. The dendritic axial resistance and sodium conductances have been modified to better fit experimental results [1, 2, 3]. For example, in the modified model, backpropagation of dendritic action potentials requires sodium channel activation, and fails if those channels are blocked [1]. The MS neuron was activated by simulated AMPA/NMDA and GABAergic synaptic inputs [8], or by somatic current injections. Computational and experimental investigation: In this study we compare the effect of FS and MS synaptic inhibition on the backpropagation of action potentials in the MS model. Preliminary results suggest that GABAerigic inputs in distal dendrites can decrease the backpropagating action potential, and thus can reduce dendritic calcium levels, even though the cell is still spiking in the soma. These findings might suggest that feedback inhibition can control how prone the neighbouring MS neurons will be to plastic changes. These model predictions are further tested in experiments. The effect of GABAergic input on backpropagation of action potentials is investigated using two-photon calcium imaging from spines and dendrites on striatal neurons.

Dendritic properties of turtle pyramidal neurons.

The six-layered mammalian neocortex evolved from the three-layered paleocortex, which is retained in present-day reptiles such as the turtle. Thus the turtle offers an opportunity to examine which cellular and circuit properties are fundamental to cortical function. We characterized the dendritic properties of pyramidal neurons in different cortical regions of mature turtles, Pseudemys scripta elegans, using whole cell recordings and calcium imaging from the axon, soma, and dendrites in a slice preparation. The firing properties, in response to intrasomatic depolarization, resembled those previously recorded with sharp electrodes in this preparation. Somatic spikes led to active backpropagating high-amplitude dendritic action potentials and intracellular calcium ion concentration ([Ca2+]i) changes at all dendritic locations, suggesting that both backpropagation and dendritic voltage-gated Ca2+ channels are primitive traits. We found no indication that Ca2+ spikes could be evoked in the dendrites, but fast Na+ spikes could be initiated there following intradendritic stimulation. Several lines of evidence indicate that fast, smaller-amplitude somatic spikes ("prepotentials") that are easily recorded in this preparation are generated in the axon. Most synaptically activated [Ca2+]i changes resulted from Ca2+ entry through voltage-gated channels. In some cells synaptic stimulation evoked a delayed Ca2+ wave due to release from internal stores following activation of metabotropic glutamate receptors. With some small differences these properties resemble those of pyramidal neurons in mammalian species. We conclude that spike backpropagation, dendritic Ca2+ channels, and synaptically activated Ca2+ release are primitive and conserved features of cortical pyramidal cells, and therefore likely fundamental to cortical function.

Dendritic action potentials connect distributed dendrodendritic microcircuits

Lateral inhibition of cells surrounding an excited area is a key property of sensory systems, sharpening the preferential tuning of individual cells in the presence of closely related input signals. In the olfactory pathway, a dendrodendritic synaptic microcircuit between mitral and granule cells in the olfactory bulb has been proposed to mediate this type of interaction through granule cell inhibition of surrounding mitral cells. However, it is becoming evident that odor inputs result in broad activation of the olfactory bulb with interactions that go beyond neighboring cells. Using a realistic modeling approach we show how backpropagating action potentials in the long lateral dendrites of mitral cells, together with granule cell actions on mitral cells within narrow columns forming glomerular units, can provide a mechanism to activate strong local inhibition between arbitrarily distant mitral cells. The simulations predict a new role for the dendrodendritic synapses in the multicolumnar organization of the granule cells. This new paradigm gives insight into the functional significance of the patterns of connectivity revealed by recent viral tracing studies. Together they suggest a functional wiring of the olfactory bulb that could greatly expand the computational roles of the mitral-granule cell network.