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

Abstract

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.

Disentanglement of local field potential sources by independent component analysis

“…Most likely, slow dendritic currents, which cannot be separated from the synaptic ones, are integral part of each isolated generator. In parallel studies (Makarova et al 2008) we found that a major factor defining the amplitude and spatial distribution of aggregate postsynaptic currents is central spatial cancellation within postsynaptic membranes of individual membranes. For widely distributed currents this phenomenon becomes especially significant even overcoming the influence of the above mentioned electrotonic parameters (Makarova et al 2010), such as those produced by axonal fields of inhibitory interneurons in the stratum radiatum (Somogyi and Klausberger 2005).…”

“…The body temperature was maintained at 37°C. The surgical and stereotaxic procedures were described elsewhere (Canals et al 2005;Makarova et al 2008). Concentric stimulating electrodes were positioned in the ipsilateral CA3 and in the perforant pathway for orthodromic activation of the CA1 pyramidal and dentate granule cell populations, respectively.…”

“…ICA has been used in surface electroencephalography to identify and separate coherent activity in groups of adjacent electrodes (see, e.g., Bell and Sejnowski 1995;Makeig et al 2004;Jung et al 2005;Castellanos and Makarov 2006). However, the heterogeneous electrical properties of the conducting medium, spatial cancellation and frequency scaling of currents in the volume conductor (López-Aguado et al 2001;Bédard et al 2004;Makarova et al 2008) limit its utility to the gross localization of large electrical sources of unknown cellular origin. These restrictive factors are less relevant in intracerebral local field potential (LFP) studies (Tanskanen et al 2005).…”

Sustained increase of spontaneous input and spike transfer in the CA3-CA1 pathway following long-term potentiation in vivo

“…and placed in a stereotaxic device. Surgical and stereotaxic procedures were performed as previously described (Canals et al, 2005; Makarova et al, 2008). A stimulating electrode was placed in the ipsilateral CA3 region for orthodromic activation of CA1.…”

Current Source Density Reconstruction from Incomplete Data

“…For simplicity, we assume σ to be a constant scalar (isotropic, homogeneous medium), although in general this condition need not hold, and the assumption of a purely resistive medium may not even be valid (Holsheimer, 1987;Ibarz, Makarova, & Herreras, 2006;Logothetis, Kayser, & Oeltermann, 2007;Makarova, Gómez-Galán & Herreras, 2008). One consequence of equation 1.1 is nonlocality:…”