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

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.