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The Journal of Neuroscience, April 13, 2005, 25(15):3952-3961; doi:10.1523/JNEUROSCI.0491-05.2005

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Neurobiology of Disease
Optical Current Source Density Analysis in Hippocampal Organotypic Culture Shows That Spreading Depression Occurs with Uniquely Reversing Currents

Phillip E. Kunkler,¹ Raymond E. Hulse,¹ Michael W. Schmitt,¹ Charles Nicholson,³ and Richard P. Kraig^1,2

Departments of ¹Neurology and ²Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois 60637, and ³Department of Physiology and Neuroscience, New York University, New York, New York 10016

Spreading depression (SD) involves current flow through principal neurons, but the pattern of current flow over the expanse of susceptible tissues or individual principal neurons remains undefined. Accordingly, tissue and single cell maps made from digital imaging of voltage-sensitive dye changes in hippocampal organotypic cultures undergoing SD were processed via optical current source density analysis to reveal the currents associated with pyramidal neurons. Two distinctive current flow patterns were seen. The first was a trilaminar pattern (420 µm²) that developed with the onset of SD in CA3 pyramidal neurons, in which SD most often began. This initial pattern comprised a somatic current sink with current sources to either side in the dendrites that lasted for seconds extending into the first aspect of the classical "inverted saddle" interstitial direct current waveform of SD. Next, the somatic sink backpropagated at a speed of millimeters per minute into the proximal dendrites, resulting in a reversal of the initial current flow pattern to its second orientation, namely dendritic sinks associated with a somatic source. The latter persisted for the remainder of SD in CA3 and was the only pattern seen in CA1, in which SD was rarely initiated. This backpropagating SD current flow resembles that of activity-dependent synaptic activation. Retrograde and associative signaling via principal neuron current flow is a key means to affect tissue function, including synaptic activation and, by extension, perhaps SD. Such current-related postsynaptic signaling might not only help explain SD but also neuroprotection and migraine, two phenomena increasingly recognized as being related to SD.

Key words: migraine; ischemic tolerance; neuroprotection; reaction-diffusion; inhibition; dendrite

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Received Feb 4, 2005; revised March 15, 2005; accepted March 15, 2005.

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