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Journal of Neuroscience, Vol 16, 2226-2237, Copyright © 1996 by Society for Neuroscience
Changes in action potential duration alter reliance of excitatory synaptic transmission on multiple types of Ca2+ channels in rat hippocampus
DB Wheeler, A Randall and RW Tsien
Neurosciences Program, Stanford University School of Medicine, California 94305, USA.
It has been established that multiple types of Ca2+ channels participate in
triggering neurotransmitter release at central synapses, but there is
uncertainty about the nature of their combined actions. We investigated
synaptic transmission at CA3-CA1 synapses of rat hippocampal slices and
asked whether the dependence on omega-CTx-GVIA- sensitive N-type channels
and omega-Aga-IVA-sensitive P/Q-type Ca2+ channels can be altered by
physiological mechanisms. The reliance on multiple types of Ca2+ channels
was not absolute but depended strongly on the amount of Ca2+ influx through
individual channels, which was manipulated by prolonging the presynaptic
action potential with the K+ channel blocker 4-aminopyridine (4-AP) and by
varying the extracellular Ca2+ concentration ([Ca2+]o). We quantified the
influence of spike broadening on Ca2+ influx through various Ca2+ channels
by imposing mock action potentials on voltage-clamped cerebellar granule
neurons. In field recordings of the EPSP in hippocampal slices, action
potential prolongation increased the EPSP slope by 2-fold and decreased its
reliance on either N-type or P/Q-type Ca2+ channels. The inhibition of
synaptic transmission by N-type channel blockade was virtually eliminated
in the presence of 4-AP, but it could be restored by lowering [Ca2+]o.
These results rule out a scenario in which a significant fraction of
presynaptic terminals rely solely on N-type channels to trigger
transmission. The change in sensitivity to the neurotoxins with 4-AP could
be explained in terms of a nonlinear relationship between Ca2+ entry and
synaptic strength, which rises steeply at low [Ca2+]o, but approaches
saturation at high [Ca2+]o. This relationship was evaluated experimentally
by varying [CA2+]o in the absence and presence of 4-AP. One consequence of
this relationship is that down-modulation of presynaptic Ca2+ channels by
various modulators would increase the relative impact of spike broadening
greatly.
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