Back-propagating Dendritic Action Potentials Research Articles

Benzamil inhibits neuronal and heterologously expressed small conductance Ca2+-activated K+ channels

Small conductance Ca2+-activated K+ (SK) channels are expressed throughout the soma and dendrites of pyramidal neurons in the neocortex and hippocampal formation, where they participate in the local regulation of membrane excitability and synaptic signals. Through their inter-play with Ca2+ channels, SK channels regulate Ca2+ influx triggered by back-propagating action potentials in dendrites. Inhibition of SK channels affects both the amplitude and duration of Ca2+ transients, but the role of Ca2+ clearance mechanisms and their link to SK channel activity has not been established. Here we report the effect of the Na+/Ca2+ exchanger (NCX) inhibitor benzamil on Ca2+ extrusion and SK channels in the regulation of dendritic Ca2+ signals. Benzamil increased the duration and amplitude of dendritic Ca2+ transients elicited by back-propagating action potentials in hippocampal pyramidal neurons. This data is consistent with previous studies with SK channel blockers and suggests that benzamil inhibits SK channels in addition to the Na+/Ca2+ exchanger. Here we show that indeed both the neuronal SK-mediated IAHP current and the currents mediated by heterologously expressed SK channels were inhibited by benzamil. The inhibition of recombinant SK channels was seen with different K+ concentration gradients, and was stronger at negative voltages. The suppression of SK channels by benzamil is consistent with previous findings on the modulation of Ca2+ signals by SK channels in neurons. We additionally show that benzamil inhibits neuronal voltage-gated calcium currents. The results prompt a careful reassessment of the effects of benzamil on Ca2+ transients in native systems, given the spectrum of ion channels and exchangers this compound targets within a similar range of concentrations.

Etomidate Reduces Initiation of Backpropagating Dendritic Action Potentials: Implications for Sensory Processing and Synaptic Plasticity During Anesthesia

Anesthetics may induce specific changes that alter the balance of activity within neural networks. Here we describe the effects of the GABA(A) receptor potentiating anesthetic etomidate on sensory processing, studied in a cerebellum-like structure, the electrosensory lateral line lobe (ELL) of mormyrid fish, in vitro. Previous studies have shown that the ELL integrates sensory input and removes predictable features by comparing reafferent sensory signals with a descending electromotor command-driven corollary signal that arrives in part through parallel fiber synapses with the apical dendrites of GABAergic interneurons. These synapses show spike timing-dependent depression when presynaptic activation is associated with postsynaptic backpropagating dendritic action potentials. Under etomidate, almost all neurons become tonically hyperpolarized. The threshold for action potential initiation increased for both synaptic activation and direct intracellular depolarization. Synaptically evoked inhibitory postsynaptic potentials (IPSPs) were also strongly potentiated and prolonged. Current source density analysis showed that backpropagation of action potentials through the apical dendritic arborization in the molecular layer was reduced but could be restored by increasing stimulus strength. These effects of etomidate were blocked by bicuculline or picrotoxin. It is concluded that etomidate affects both tonic and phasic inhibitory conductances at GABA(A) receptors and that increased shunting inhibition at the level of the proximal dendrites also contributes to increasing the threshold for action potential backpropagation. When stimulus strength is sufficient to evoke backpropagation, repetitive association of synaptic excitation with postsynaptic action potential initiation still results in synaptic depression, showing that etomidate does not interfere with the molecular mechanism underlying plastic modulation.

Novel dynamics of dendritic integration in the high conductance state of cortical neurons

Neocortical neurons in vivo operate in a high-conductance state which may affect the dynamics of dendritic integration, but this aspect remains only barely characterized. We investigated this problem by using biophysical models of morphologically reconstructed neocortical pyramidal neurons in which isolated and paired synaptic events were studied according to their dendritic location. We show that during active states, there is an ongoing dynamics of randomly occurring forward- and back-propagating dendritic action potentials. This dynamics determinantly impacts on how individual or paired synaptic events interact, leading to a type of integrative behavior which is different from classical models of dendritic integration.

Arachidonic Acid Reciprocally Alters the Availability of Transient and Sustained Dendritic K+Channels in Hippocampal CA1 Pyramidal Neurons

The dendrites of hippocampal CA1 pyramidal cell dendrites express a high density of transient A-type K(+) channels, which play a critical role in the back-propagation of action potentials and in the determination of dendritic excitability. Recently, arachidonic acid and its nonmetabolizable analogue 5,8,11,14-eicosatetraynoic acid (ETYA) were shown to block transient K(+) channels in the somata of these cells (), but to have little effect on the somatic action potential. In the present study we have investigated the effects of arachidonic acid and ETYA on the gating of channels and the excitability of the apical dendrites of CA1 pyramidal neurons. We found not only a block of transient K(+) channels, but also an enhancement of sustained outward currents. The sustained currents consisted of at least two distinct channel types. The larger conductance channel (>50 pS) was identified as a K(+) channel. Arachidonic acid greatly enhanced the amplitude of back-propagating dendritic action potentials (>200 micrometer from the soma) but did not result in sustained depolarizations of the dendrites similar to those seen with 4-aminopyridine (4-AP) application. In fact, arachidonic acid reduced dendritic excitability when applied after 4-AP. Thus, arachidonic acid appears to cause a shift of available channels from the fast, transient type to the slower, sustained types. The net effect appears to be an enhancement of dendritic action potential amplitude that occurs without compromising the electrical stability of the dendrites.

Neuromodulation of dendritic action potentials.

The extent to which regenerative action potentials invade hippocampal CA1 pyramidal dendrites is dependent on both recent activity and distance from the soma. Previously, we have shown that the amplitude of back-propagating dendritic action potentials can be increased by activating either protein kinase A (PKA) or protein kinase C (PKC) and a subsequent depolarizing shift in the activation curve for dendritic K+ channels. Physiologically, an increase in intracellular PKA and PKC would be expected upon activation of beta-adrenergic and muscarinic acetylcholine receptors, respectively. Accordingly, we report here that activation of either of these neurotransmitter systems results in an increase in dendritic action-potential amplitude. Activation of the dopaminergic neurotransmitter system, which is also expected to raise intracellular adenosine 3',5'-cyclic monophosphate (cAMP) and PKA levels, increased action-potential amplitude in only a subpopulation of neurons tested.

Protein Kinase C Activation Decreases Activity-Dependent Attenuation of Dendritic Na+ Current in Hippocampal CA1 Pyramidal Neurons

Action potentials recorded from the soma of CA1 pyramidal neurons remain relatively uniform in amplitude during repetitive firing. In contrast, the amplitudes of back-propagating action potentials in dendrites decrease progressively during a spike train. This activity-dependent decrease in amplitude is dependent on the frequency of firing during the train and distance from the soma. Previously, we described a property of Na+ channels that provides a plausible mechanism for the activity dependence of the amplitude of the dendritic action potentials: available Na+ current decreases during trains of action potentials through an inactivation, distinct from fast inactivation, that appears rapid in onset, but slow and voltage-dependent in its recovery. In this study we found that activation of protein kinase C by phorbol esters decreased this activity-dependent inactivation of pharmacologically isolated Na+ current in cell-attached dendritic, but not somatic, patches. Similarly in whole cell recordings phorbol esters decreased the attenuation of back-propagating dendritic action potentials during trains. These results indicate a novel effect of protein kinase C on the dendritic Na+ channel and further support the hypothesis that the activity dependence of the dendritic action potentials is derived from the inactivation properties of Na+ channels.

A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.

The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.