In CA1 pyramidal neurons of the hippocampus, calcium-dependent spikes occur in vivo during specific behavioral states and may be enhanced during epileptiform activity. However, the mechanisms that control calcium spike initiation and repolarization are poorly understood. Using dendritic and somatic patch-pipette recordings, we show that calcium spikes are initiated in the apical dendrites of CA1 pyramidal neurons and drive bursts of sodium-dependent action potentials at the soma. Initiation of calcium spikes at the soma was suppressed in part by potassium channels activated by sodium-dependent action potentials. Low-threshold, putative D-type potassium channels [blocked by 100 microM 4-aminopyridine (4-AP) and 0.5-1 microM alpha-dendrotoxin (alpha-DTX)] played a prominent role in setting a high threshold for somatic calcium spikes, thus restricting initiation to the dendrites. DTX- and 4-AP-sensitive channels were activated during sodium-dependent action potentials and mediated a large component of their afterhyperpolarization. Once initiated, repetitive firing of calcium spikes was limited by activation of putative BK-type calcium-activated potassium channels (blocked by 250 microM tetraethylammonium chloride, 70 nM charybdotoxin, or 100 nM iberiotoxin). Thus, the concerted action of calcium- and voltage-activated potassium channels serves to focus spatially and temporally the membrane depolarization and calcium influx generated by calcium spikes during strong, synchronous network excitation.

We performed simultaneous patch-electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady-state somatic voltage changes occurred at a distance of 238 µm from the soma in control and 409 µm after blocking the hyperpolarization-activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100-fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both. The complex processing of synaptic inputs that occurs throughout a neuron greatly depends on the passive membrane resistivity (R m ) of the neuronal membrane and the internal resistivity (R i ) of the dendrites. These properties, together with dendritic morphology, provide the foundation upon which synaptic integration and action potential initiation take place. Despite their importance, we know little about the values of these parameters, in part because they are difficult to estimate on the basis of somatic recordings. As a result, we do not know how many distal synaptic inputs are needed to trigger an action potential, because the amount of depolarization they produce and the extent to which they attenuate on their way to the soma are not known. Likewise, we cannot predict with precision the time course over which synaptic potentials, when generated in dendrites, will summate in the soma and axon. One way to address these problems is to develop accurate computer models of neurons. These require, however, that we determine the electrical properties of dendrites.

During low-frequency firing, action potentials actively invade the dendrites of CA1 pyramidal neurons. At higher firing rates, however, activity-dependent processes result in the attenuation of back-propagating action potentials, and propagation failures occur at some dendritic branch points. We tested two major hypotheses related to this activity-dependent attenuation of back-propagating action potentials: (1) that it is mediated by a prolonged form of sodium channel inactivation and (2) that it is mediated by a persistent dendritic shunt activated by backpropagating action potentials. We found no evidence for a persistent shunt, but we did find that cumulative, prolonged inactivation of sodium channels develops during repetitive action potential firing. This inactivation is significant after a single action potential and continues to develop during several action potentials thereafter, until a steady-state sodium current is established. Recovery from this form of inactivation is much slower than its induction, but recovery can be accelerated by hyperpolarization. The similarity of these properties to the time and voltage dependence of attenuation and recovery of dendritic action potentials suggests that dendritic sodium channel inactivation contributes to the activity dependence of action potential back-propagation in CA1 neurons. Hence, the biophysical properties of dendritic sodium channels will be important determinants of action potential-mediated effects on synaptic integration and plasticity in hippocampal neurons. Key words: dendrite; action potential; sodium channels; synaptic integration; pyramidal neuron; activity dependentRecent experiments using simultaneous somatic and dendritic patch-pipette recordings have shown that action potentials are normally initiated in the axon and back-propagate into the dendrites of many types of C NS neurons (for review, see Stuart et al., 1997). These back-propagating action potentials are likely to provide an important spatial signal that influences ongoing synaptic integration and allows for postsynaptic firing in the axon to be associated with presynaptic activity. For example, the induction of activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression depend critically on the timing of pre-and postsynaptic inputs (Levy and Steward, 1983;Markram et al., 1997), and one form of LTP has been shown to be blocked by preventing action potentials from back-propagating into the dendrites of hippocampal pyramidal neurons (Magee and Johnston, 1997). These findings demonstrate the importance of understanding the factors that determine the extent and pattern of action potential back-propagation in pyramidal neuron dendrites.Action potential back-propagation in CA1 dendrites is complex. At low frequencies action potentials invade most of the dendritic tree in an active fashion, whereas at higher frequencies action potentials attenuate more and may fail to actively propagate into much of the dendritic tree (C allaway and Ross,...

Sodium channels in the somata and dendrites of hippocampal CA1 pyramidal neurons undergo a form of long-lasting, cumulative inactivation that is involved in regulating back-propagating action potential amplitude and can influence dendritic excitation. Using cell-attached patch-pipette recordings in the somata and apical dendrites of CA1 pyramidal neurons, we determined the properties of slow inactivation on response to trains of brief depolarizations. We find that the amount of slow inactivation gradually increases as a function of distance from the soma. Slow inactivation is also frequency and voltage dependent. Higher frequency depolarizations increase both the amount of slow inactivation and its rate of recovery. Hyperpolarized resting potentials and larger command potentials accelerate recovery from slow inactivation. We compare this form of slow inactivation to that reported in other cell types, using longer depolarizations, and construct a simplified biophysical model to examine the possible gating mechanisms underlying slow inactivation. Our results suggest that sodium channels can enter slow inactivation rapidly from the open state during brief depolarizations or slowly from a fast inactivation state during longer depolarizations. Because of these properties of slow inactivation, sodium channels will modulate neuronal excitability in a way that depends in a complicated manner on the resting potential and previous history of action potential firing.

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