Presynaptic Ca2+ channels and neurotransmitter release at the terminal of a mouse cortical neuron.

Regional variation in synaptic efficacy is an important determinant of associative processing as information flows through major circuits of the brain. The perforant path is the principal route of entry from cortex to the hippocampus and contains the first synapse in the cortical-hippocampal projection pathway. We used optical imaging techniques to analyze presynaptic Ca(2+) entry and neurotransmitter release at synapses in the medial perforant path linking stellate neurons located in layer II of the entorhinal cortex to granule cells in the dentate gyrus. Similar to other excitatory central synapses, the relationship between neurotransmitter release and the amount of Ca(2+) influx can be best described by a Hill equation with a Hill coefficient of 3.5. Our Ca(2+) channel toxin studies indicate that P/Q-type channels are the predominant Ca(2+) source triggering neurotransmitter release in this pathway, as shown by a potent inhibition of Ca(2+) entry and synaptic transmission by the P/Q-type channel blocker omega-agatoxin IVA. However, compared with the downstream hippocampal pyramidal neuron CA3-CA1 synapse, neurotransmitter release was less sensitive to the N-type Ca(2+) channel blocker omega-conotoxin GVIA, although the amount of N-type Ca(2+) current is comparable. The contribution of N-type channels to neurotransmitter release approximates that found at the CA3-CA1 synapse when tested under lower [Ca(2+)](o), which effectively reduces the size of the Ca(2+) microdomain surrounding each channel. These results suggest that P/Q-type channels are more closely associated with release machinery then N-type channels at this synapse and that cooperativity differences for each channel subtype may characterize variations in signaling at central synapses.