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Pharmacologically induced calcium oscillations protect neurons from increases in cytosolic calcium after trauma

Donna M Geddes-Klein1, Gul Serbest, Mahlet N Mesfin

  • 1Department of Bioengineering, University of Pennsylvania, Philadelphia, 19104, USA. dmgeddes@saes.upenn.edu

Journal of Neurochemistry
|March 17, 2006
PubMed

Insights

Developing neurons with reduced inhibition show less calcium response to mechanical injury. This desensitization involves NMDA receptor uncoupling, impacting immature brain sensitivity to traumatic brain injury.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Traumatic Brain Injury Research

Background:

  • Elevated cytosolic calcium ([Ca(2+)](i)) is a key factor in traumatic brain injury (TBI) sequelae.
  • Developmental changes in neuronal inhibition, leading to spontaneous [Ca(2+)](i) oscillations, may alter mechanical injury sensitivity.
  • The precise mechanisms linking developmental calcium signaling and mechanical trauma response remain unclear.

Purpose of the Study:

  • To investigate the mechanism of stretch-induced [Ca(2+)](i) transients in developing neurons.
  • To determine how reduced inhibition, mimicking developmental states, affects neuronal response to mechanical stretch.
  • To elucidate the role of NMDA receptors and cytoskeletal interactions in mechanical desensitization.

Main Methods:

  • Utilized an in vitro model of mechanical trauma applying uniaxial strain to cultured cortical neurons.
  • Measured neuronal response via increases in cytosolic calcium ([Ca(2+)](i)).
  • Examined stretch-induced [Ca(2+)](i) transients in 18-days in vitro (DIV) neurons, including those with bicuculline-induced [Ca(2+)](i) oscillations, and employed NMDA receptor antagonists and actin cytoskeleton disruption.

Main Results:

  • Stretch-induced [Ca(2+)](i) increases in 18-DIV neurons were attenuated by NMDA receptor antagonism (APV) or actin depolymerization.
  • Blocking synaptic NMDA receptors significantly reduced the [Ca(2+)](i) transient following stretch.
  • Neurons with pharmacologically induced [Ca(2+)](i) oscillations exhibited a substantially reduced peak [Ca(2+)](i) response to stretch, indicating mechanical desensitization.

Conclusions:

  • Reduced neuronal inhibition, characterized by spontaneous [Ca(2+)](i) oscillations, desensitizes neurons to mechanical stretch.
  • Protein Kinase C (PKC)-mediated uncoupling of NMDA receptors from spectrin contributes to this mechanical desensitization.
  • These findings offer insights into how developmental calcium signaling influences immature brain sensitivity to trauma.

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