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Spreading depression (SD), a wave of neuron activity related to migraine and the ischaemic penumbra, features a moving shell of extracellular negative potential shift (V(o)) whose generators are poorly understood. We investigated its subcellular correlates in the hippocampal CA1 in vivo by localizing the neuron domains that generate transmembrane current (I(m)) using field analysis, and the local changes of tissue resistivity, a major determinant of extracellular current flow. A large increase of tissue resistivity occurred in times and dendritic strata displaying large V(o), albeit with different rates. Typically, SD is composed of basal and apical dendritic components. The apical SD lasts much longer, while it becomes gradually restricted to a narrow dendritic region. Strikingly, pyramidal cells displayed a strong surge of inward current only when SD affected a small dendritic region. However, when the V(o) signal covered most of the main neuron axis, only smaller surges of inward current developed at the outer dendritic rims of a wide null current zone. Computational reconstruction showed that this effect was due to strong spatial cancellation of the inward and outward currents in SD-activated isopotential and shunted regions of individual neurons. Consequently, despite former accounts of large conductance increase, the net I(m) is small and the large DeltaV(o) amplitude mostly due to increased tissue resistivity. The particular subcellular evolution indicates an initial explosive opening of conductance along most of the pyramidal neuron followed by a wave-like centripetal closure towards the apical dendrites. The applicability of these mechanisms to SD in other brain regions is discussed.

Recent studies on the initiation and propagation of dendritic spikes have modified the classical view of postsynaptic integration. Earlier we reported that subthreshold currents and spikes recruited by synaptic currents play a critical role in defining outputs following synchronous activation. Experimental factors strongly condition these currents due to their nonlinear behaviour. Hence, we have performed a detailed parametric study in a CA1 pyramidal cell model to explore how different variables interact and initiate dendritic spiking, and how they influence cell output. The input pattern, the relative excitability of axon and dendrites, the presence/modulation of voltage-dependent channels, and inhibition were cross analysed. Subthreshold currents and spikes on synaptically excited branches fired spikes in other branches to jointly produce different modalities of apical shaft spiking with a variable impact on cell output. Synchronous activation initiated a varying number and temporal scatter of firing branches that produced in the apical shaft-soma axis nonpropagating spikes, pseudosaltatory or continuous forward conduction, or backpropagation. As few as 6-10 local spikes within a time window of 2 ms ensure cell output. However, the activation mode varied extremely when two or more variables were cross-analysed, becoming rather unpredictable when all the variables were considered. Spatially clustered inputs and upper modulation of dendritic Na(+) or Ca(2+) electrogenesis favour apical decision. In contrast, inhibition biased the output decision toward the axon and switched between dendritic firing modes. We propose that dendrites can discriminate input patterns and decide immediate cell output depending on the particular state of a variety of endogenous parameters.