title: Presynaptic calcium influx controls neurotransmitter release in part by regulating the effective size of the readily releasable pool.
abstract: The steep calcium dependence of synaptic strength that has been observed at many synapses is thought to reflect a calcium dependence of the probability of vesicular exocytosis (p), with the cooperativity of three to six corresponding to the multiple calcium ion binding sites on the calcium sensor responsible for exocytosis. Here we test the hypothesis that the calcium dependence of the effective size of the readily releasable pool (RRP) also contributes to the calcium dependence of release at the calyx of Held synapse in mice. Using two established methods of quantifying neurotransmitter release evoked by action potentials (effective RRP), we find that when calcium influx is changed by altering the external calcium concentration, the calcium cooperativity of p is insufficient to account for the full calcium dependence of EPSC size; the calcium dependence of the RRP size also contributes. Reducing calcium influx by blocking R-type voltage-gated calcium channels (VGCCs) with Ni(2+), or by blocking P/Q-type VGCCs with ω-agatoxin IVA also changes EPSC amplitude by reducing both p and the effective RRP size. This suggests that the effective RRP size is dependent on calcium influx through VGCCs. Furthermore, activation of GABAB receptors, which reduces presynaptic calcium through VGCCs without other significant effects on release, also reduces the effective RRP size in addition to reducing p. These findings indicate that calcium influx regulates the RRP size along with p, which contributes to the calcium dependence of synaptic strength, and it influences the manner in which presynaptic modulation of presynaptic calcium channels affects neurotransmitter release.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Thanawala
authors.forename: Wade G
authors.initials: WG
authors.lastname: Regehr
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D001703:Biophysics; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003198:Computer Simulation; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009532:Nickel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010721:Phosphinic Acids / Q000494:pharmacology; D011149:Pons / Q000166:cytology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D018377:Neurotransmitter Agents; D010721:Phosphinic Acids; D011412:Propanolamines; D020867:omega-Agatoxin IVA; C085075:CGP 55845A; D009532:Nickel; D001418:Baclofen; D002118:Calcium