Abstracts

RATIONALE: The tottering mouse (tg, a1A subunit mutation) inherits altered P/Q type calcium channels and spontaneous thalamocortical spike-wave epilepsy. Since this channel type mediates transmitter release at most synaptic terminals, the mechanisms that determine why specific neural circuits are preferentially affected are unclear. METHODS: We employed fluorescence imaging of an accessible cortical axon terminal in brain slices to investigate presynaptic Ca currents and synaptic transmission in the lateral perforant path in tg mice, a major input from entorhinal cortex to the hippocampus. RESULTS: In wild type mice, blocking N-type Ca channels with w-CgTx GVIA revealed that about 35% of presynaptic Ca current is N-type, but the toxin had only a minor (11% reduction) effect on neurotransmitter release compared to other central synapses. Blocking both N and P/Q-type channels with w-CgTx MVIIC greatly inhibited synaptic transmission (87%) and revealed that P/Q-type channels contribute about 32% of the total Ca current. Our previous study found a compensatory mechanism at the CA3-CA1 synapse in tg mice where N-type channels replace the mutated P/Q-type as a predominant Ca source for neurotransmitter release, and blocking N-type channels completely eliminated synaptic transmission. In contrast, at this synapse, blocking N-type channels resulted in only 40% reduction of release. The ratio of presynaptic Ca channel subtypes in tg mice is also different from those in the CA3-CA1 synapse. The total Ca influx is about 48% N-type, 17% P/Q-type and the rest is resistant to the Ca channel toxin w-CgTx GVIA and w-CgTx MVIIC. Furthermore, there is a significant fraction of residual synaptic transmission after application of the two channel toxins, suggesting that a toxin-resistant type of Ca channels is involved in neurotransmitter release. CONCLUSIONS: Our results indicate that different synapses respond differently to the same molecular defect of P/Q-type channels. Sponsored by the American Epilepsy Society/Milken Family Foundation and NIH NS29709.