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The Journal of Neuroscience, January 1, 2000, 20(1):163-170

Presynaptic Ca²⁺ Influx at a Mouse Central Synapse with Ca²⁺ Channel Subunit Mutations

Jing Qian and Jeffrey L. Noebels

Department of Neurology, Baylor College of Medicine, Houston, Texas 77030

Genetic alterations in Ca²⁺ channel subunits can be used to study the interaction among channel subunits and their roles in channel function. P/Q- and N-type Ca²⁺ channels reside at the presynaptic terminal and control the release of neurotransmitter at mammalian central synapses. We used fluorescence imaging techniques to investigate presynaptic Ca²⁺ currents and neurotransmitter release at hippocampal Schaffer collateral synapses in both tottering (tg, _1A subunit) and lethargic (lh, ₄ subunit) mutant mice. Application of selective toxins revealed a large reduction in presynaptic P/Q-type Ca²⁺ transients, from 39% of total in +/+ mice to 6% in tg/tg mice, whereas the proportion of N-type increased from 35 to 68%, respectively. Neurotransmitter release in the tg/tg mutant relied almost exclusively on N-type channels, as shown by the complete blockade of synaptic transmission with -conotoxin GVIA. Remarkably, loss of 4, a subunit predicted to regulate the subcellular targeting and modulation of both P/Q- and N-type channels, resulted in no significant difference in the ratio of Ca²⁺ channel subtypes or Ca²⁺ dependence of neurotransmitter release in lethargic mice. G-protein-mediated inhibition of Ca²⁺ channels was also unaltered. These results indicate that a profound decrease in presynaptic P/Q-type currents leads to dependence of neurotransmitter release on N-type channels. In contrast, absence of ₄ appears not to compromise either P/Q- or N-type channel function at this hippocampal synapse, implicating rescue of presynaptic Ca²⁺ currents by other available  subunits. The present study reveals compensatory molecular mechanisms in the regulation of presynaptic Ca²⁺ entry and neurotransmitter release.

Key words: hippocampus; presynaptic terminal; magnesium green; transmitter release; PPF; power function; cooperativity

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Copyright © 2000 Society for Neuroscience  0270-6474/0/201163-08$05.00/0

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