Variations in tissue resistivity and in the extension of activated neuron domains shape the voltage signal during spreading depression in the CA1 in vivo.

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.