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This Article Full Text Full Text (PDF) All Versions of this Article: 101/3/1351    most recent 91012.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kunjilwar, K. K. Articles by Walters, E. T. Search for Related Content PubMed PubMed Citation Articles by Kunjilwar, K. K. Articles by Walters, E. T.

Long-Lasting Hyperexcitability Induced by Depolarization in the Absence of Detectable Ca²⁺ Signals

Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, Texas

Submitted 9 September 2008; accepted in final form 11 January 2009

Abstract

Learning and memory depend on neuronal alterations induced by electrical activity. Most examples of activity-dependent plasticity, as well as adaptive responses to neuronal injury, have been linked explicitly or implicitly to induction by Ca²⁺ signals produced by depolarization. Indeed, transient Ca²⁺ signals are commonly assumed to be the only effective transducers of depolarization into adaptive neuronal responses. Nevertheless, Ca²⁺-independent depolarization-induced signals might also trigger plastic changes. Establishing the existence of such signals is a challenge because procedures that eliminate Ca²⁺ transients also impair neuronal viability and tolerance to cellular stress. We have taken advantage of nociceptive sensory neurons in the marine snail Aplysia, which exhibit unusual tolerance to extreme reduction of extracellular and intracellular free Ca²⁺ levels. The axons of these neurons exhibit a depolarization-induced memory-like hyperexcitability that lasts a day or longer and depends on local protein synthesis for induction. Here we show that transient localized depolarization of these axons in an excised nerve–ganglion preparation or in dissociated cell culture can induce short- and intermediate-term axonal hyperexcitability as well as long-term protein synthesis–dependent hyperexcitability under conditions in which Ca²⁺ entry is prevented (by bathing in nominally Ca²⁺ -free solutions containing EGTA) and detectable Ca²⁺ transients are eliminated (by adding BAPTA-AM). Disruption of Ca²⁺ release from intracellular stores by pretreatment with thapsigargin also failed to affect induction of axonal hyperexcitability. These findings suggest that unrecognized Ca²⁺-independent signals exist that can transduce intense depolarization into adaptive cellular responses during neuronal injury, prolonged high-frequency activity, or other sustained depolarizing events.