Jeffrey C. Magee

K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons

Pyramidal neurons receive tens of thousands of synaptic inputs on their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. Surprisingly, there turns out to be a very high density of transient A-type potassium ion channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent initiation of an action potential in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce excitatory synaptic events. The channels act to prevent large, rapid dendritic depolarizations, thereby regulating orthograde and retrograde propagation of dendritic potentials.

Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons

Most neurons receive thousands of synaptic inputs onto widely spread dendrites. Because of dendritic filtering, distant synapses should have less efficacy than proximal ones. To investigate this, we characterized the amplitude and kinetics of excitatory synaptic input across the apical dendrites of CA1 pyramidal neurons using dual whole-cell recordings. We found that dendritic EPSP amplitude increases with distance from the soma, counterbalancing the filtering effects of the dendrites and reducing the location dependence of somatic EPSP amplitude. Dendritic current injections and a multi-compartmental computer model demonstrated that dendritic membrane properties have only a minor role in elevating the local EPSP. Instead a progressive increase in synaptic conductance seems to be primarily responsible for normalizing the amplitudes of individual inputs.

Characterization of single voltage‐gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons.

1. We have used dendrite‐attached patch‐clamp techniques to record single Na+ and Ca2+ channel activity from the apical dendrites (up to 350 microns away from soma) of CA1 pyramidal neurons in rat hippocampal slices (ages: 2‐8 weeks). 2. Na+ channels were found in every patch examined (range: 2 to > 20 channels per patch). Channel openings, which had a slope conductance of 15 +/‐ 0.3 pS (mean +/‐ S.E.M.), began with test commands to around ‐50 mV and consisted of both early transient channel activity and also later occurring prolonged openings of 5‐15 ms. All Na+ channel activity was suppressed by inclusion of TTX (1 microM) in the recording pipette. 3. Ca2+ channel activity was recorded in about 80% of the patches examined (range: 1 to > 10 channels per patch). Several types of channel behaviour were observed in these patches. Single channel recordings in 110 mM BaCl2, revealed an approximately 10 pS channel of small unitary current amplitude (‐0.5 pA at ‐20 mV). These channels began activating at relatively hyperpolarized potentials (‐50 mV) and ensemble averages of this low voltage‐activated (LVA) channel activity showed rapid inactivation. 4. A somewhat heterogeneous population of high voltage‐activated, moderate conductance (HVAm; approximately 17 pS), Ca2+ channel activity was also encountered. These channels exhibited a relatively large unitary amplitude (‐0.8 pA at 0 mV) and ensemble averages demonstrated moderate inactivation. The HVAm population of channels could be tentatively subdivided into two separate groups based upon mean channel open times. 5. Less frequently, HVA, large conductance (27 pS) Ca2+ channel activity (HVA1) was also observed. This large unitary amplitude (‐1.5 pA at 0 mV) channel activity began with steps to approximately 0 mV and ensemble averages did not show any time‐dependent inactivation. The dihydropyridine Ca2+ channel agonist Bay K 8644 (0.5 or 1 microM) was found to characteristically prolong these channel openings. 6. omega‐Conotoxin MVIIC (10 microM), did not significantly reduce the amount of channel activity recorded from the LVA, HVAm or HVA1 channel types in dendritic patches. In patches from somata, omega‐conotoxin MVIIC was effective in eliminating a significant amount of HVAm Ca2+ channel activity. Inclusion of 50 or 100 microM NiCl2 to the recording solution significantly reduced the amount of channel activity recorded from LVA and HVAm channel types in dendritic patches. A subpopulation of HVAm channels was, however, found to be Ni2+ insensitive. Dendritic HVA, channel activity was unaffected by these low concentrations of Ni2+.(ABSTRACT TRUNCATED AT 400 WORDS)

Dendritic integration of excitatory synaptic input

A fundamental function of nerve cells is the transformation of incoming synaptic information into specific patterns of action potential output. An important component of this transformation is synaptic integration — the combination of voltage deflections produced by a myriad of synaptic inputs into a singular change in membrane potential. There are three basic elements involved in integration: the amplitude of the unitary postsynaptic potential, the manner in which non-simultaneous unitary events add in time (temporal summation), and the addition of unitary events occurring simultaneously in separate regions of the dendritic arbor (spatial summation). This review discusses how passive and active dendritic properties, and the functional characteristics of the synapse, shape these three elements of synaptic integration.

Compartmentalized dendritic plasticity and input feature storage in neurons

Although information storage in the central nervous system is thought to be primarily mediated by various forms of synaptic plasticity, other mechanisms, such as modifications in membrane excitability, are available. Local dendritic spikes are nonlinear voltage events that are initiated within dendritic branches by spatially clustered and temporally synchronous synaptic input. That local spikes selectively respond only to appropriately correlated input allows them to function as input feature detectors and potentially as powerful information storage mechanisms. However, it is currently unknown whether any effective form of local dendritic spike plasticity exists. Here we show that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an N-methyl-d-aspartate receptor (NMDAR)-dependent regulation of dendritic Kv4.2 potassium channels. These data suggest that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatio-temporal correlation. We propose that this ‘branch strength potentiation’ represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.

Integrative Properties of Radial Oblique Dendrites in Hippocampal CA1 Pyramidal Neurons

Although radial oblique dendrites are a major synaptic input site in CA1 pyramidal neurons, little is known about their integrative properties. We have used multisite two-photon glutamate uncaging to deliver different spatiotemporal input patterns to single branches while simultaneously recording the uncaging-evoked excitatory postsynaptic potentials and local Ca2+ signals. Asynchronous input patterns sum linearly in spite of the spatial clustering and produce Ca2+ signals that are mediated by NMDA receptors (NMDARs). Appropriately timed and sized input patterns ( approximately 20 inputs within approximately 6 ms) produce a supralinear summation due to the initiation of a dendritic spike. The Ca2+ signals associated with synchronous input were larger and mediated by influx through both NMDARs and voltage-gated Ca2+ channels (VGCCs). The oblique spike is a fast Na+ spike whose duration is shaped by the coincident activation of NMDAR, VGCCs, and transient K+ currents. Our results suggest that individual branches can function as single integrative compartments.

LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites

The propagation and integration of signals in the dendrites of pyramidal neurons is regulated, in part, by the distribution and biophysical properties of voltage-gated ion channels. It is thus possible that any modification of these channels in a specific part of the dendritic tree might locally alter these signaling processes. Using dendritic and somatic whole-cell recordings, combined with calcium imaging in rat hippocampal slices, we found that the induction of long-term potentiation (LTP) was accompanied by a local increase in dendritic excitability that was dependent on the activation of NMDA receptors. These changes favored the back-propagation of action potentials into this dendritic region with a subsequent boost in the Ca2+ influx. Dendritic cell-attached patch recordings revealed a hyperpolarized shift in the inactivation curve of transient, A-type K+ currents that can account for the enhanced excitability. These results suggest an important mechanism associated with LTP for shaping signal processing and controlling dendritic function.

Dendritic potassium channels in hippocampal pyramidal neurons

Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back‐propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non‐uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium‐dependent potassium current on action potential repolarization is progressively reduced in the first 150 μm of the apical dendrites, so that action potentials recorded farther than 200 μm from the soma have no fast after‐hyperpolarization and are wider than those in the soma. The peak amplitude of back‐propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A‐type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long‐term potentiation induced by pairing EPSPs and back‐propagating action potentials.

On the Initiation and Propagation of Dendritic Spikes in CA1 Pyramidal Neurons

Under certain conditions, regenerative voltage spikes can be initiated locally in the dendrites of CA1 pyramidal neurons. These are interesting events that could potentially provide neurons with additional computational abilities. Using whole-cell dendritic recordings from the distal apical trunk and proximal tuft regions and realistic computer modeling, we have determined that highly synchronized and moderately clustered inputs are required for dendritic spike initiation: ∼50 synaptic inputs spread over 100 μm of the apical trunk/tuft need to be activated within 3 msec. Dendritic spikes are characterized by a more depolarized voltage threshold than at the soma [-48 ± 1 mV (n = 30) vs -56 ± 1 mV (n = 7), respectively] and are mainly generated and shaped by dendritic Na+ and K+ currents. The relative contribution of AMPA and NMDA currents is also important in determining the actual spatiotemporal requirements for dendritic spike initiation. Once initiated, dendritic spikes can easily reach the soma, but their propagation is only moderately strong, so that it can be modulated by physiologically relevant factors such as changes in the Vm and the ionic composition of the extracellular solution. With effective spike propagation, an extremely short-latency neuronal output is produced for greatly reduced input levels. Therefore, dendritic spikes function as efficient detectors of specific input patterns, ensuring that the neuronal response to high levels of input synchrony is a precisely timed action potential output.

State-Dependent Dendritic Computation in Hippocampal CA1 Pyramidal Neurons

Depending on the behavioral state, hippocampal CA1 pyramidal neurons receive very distinct patterns of synaptic input and likewise produce very different output patterns. We have used simultaneous dendritic and somatic recordings and multisite glutamate uncaging to investigate the relationship between synaptic input pattern, the form of dendritic integration, and action potential output in CA1 neurons. We found that when synaptic input arrives asynchronously or highly distributed in space, the dendritic arbor performs a linear integration that allows the action potential rate and timing to vary as a function of the quantity of the input. In contrast, when synaptic input arrives synchronously and spatially clustered, the dendritic compartment receiving the clustered input produces a highly nonlinear integration that leads to an action potential output that is extraordinarily precise and invariant. We also present evidence that both of these forms of information processing may be independently engaged during the two distinct behavioral states of the hippocampus such that individual CA1 pyramidal neurons could perform two different state-dependent computations: input strength encoding during theta states and feature detection during sharp waves.