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Open Access

A novel signaling pathway to facilitate synaptic transmission in the cerebral cortex

  • SM Smith1,
  • JB Bergsman2,
  • RH Scheller1 and
  • RW Tsien3
Critical Care20015(Suppl 1):P183

Received: 15 January 2001

Published: 2 March 2001


GlutamateStatus EpilepticusSynaptic TransmissionNeuronal DeathSpermidine

Excessive and uncontrolled synaptic transmission resulting in increased glutamate release has been highlighted as responsible for neuronal death in a variety of neurological conditions including head trauma, stroke and status epilepticus. We are interested in synaptic transmission and how this can be regulated at times of critical illness. Ca2+ entry is a critical signal at the synapse where it triggers exocytosis, plasticity, and gene expression. The small volume and limited accessibility of the synaptic cleft has led to the prediction that pre-and postsynaptic Ca2+ influx during neurotransmission will reduce extracellular [Ca2+] ([Ca2+]o), significantly attenuating the release probability of the synapse. Recordings in intact cortex and single synapses have demonstrated falls of one third in [Ca2+]o following moderate activity. It has been proposed that mechanisms to reduce the effect of the fall of [Ca2+]o at the synaptic cleft have a key role in sustaining neurotransmission during periods of high activity. Here we report direct electrophysiological recordings from rat cortical nerve terminals made to identify mechanisms which compensate for reductions of [Ca2+]o. We show that a novel voltage-sensitive, non-specific cation channel (NSCC) was a major contributor to the membrane current of the presynaptic terminal and that this channel was activated by decreases in [Ca2+]o. The [Ca2+]o sensor was also modulated by Mg2+, Gd3+, and spermidine, consistent with properties of identified extracellular Ca2+receptors (CaRs), and regulated the NSCC via a diffusible second messenger. We predict that the NSCC may act to counter the fall in release probability produced by physiological decreases in [Ca2+]o at the synaptic cleft, by favoring Ca2+ delivery via broadening of presynaptic action potentials. If this novel signaling pathway acts to ensure synaptic efficacy at times of excessive synaptic activity, inactivation of the pathway may provide a new route through which we can reduce glutamate excitotoxicity and so reduce neuronal death.

Authors’ Affiliations

Howard Hughes Medical Institute, Stanford, USA
Neurosciences Program, Stanford, USA
Department of Molecular and Cellular Physiology, Beckman Center, Stanford University School of Medicine, Stanford, USA


© The Author(s) 2001