Contribution of Na+/Ca2+exchange to excessive Ca2+loading in dendrites and somata of CA1 neurons in acute slice

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Abstract
Multiple Ca2+entry routes have been implicated in excitotoxic Ca2+loading in neurons and reverse‐operation of sodium–calcium exchangers (NCX) has been shown to contribute under conditions where intracellular Na+levels are enhanced. We have investigated effects of KB‐R7943, an inhibitor of reverse‐operation NCX activity, on Ca2+elevations in single CA1 neurons in acute hippocampal slices. KB‐R7943 had no significant effect on input resistance, action potential waveform, or action potential frequency adaptation, but reduced L‐type Ca2+entry in somata. Nimodipine was therefore included in subsequent experiments to prevent complication from effects of L‐type influx on evaluation of NCX activity. NMDA produced transient primary Ca2+increases, followed by propagating secondary Ca2+increases that initiated in apical dendrites. KB‐R7943 had no significant effect on primary or secondary Ca2+increases generated by NMDA. The Na+/K+ATPase inhibitor ouabain (30 μM) produced degenerative Ca2+overload that was initiated in basal dendrites. KB‐R7943 significantly reduced initial Ca2+increases and delayed the propagation of degenerative Ca2+loads triggered by ouabain, raising the possibility that excessive intracellular Na+loading can trigger reverse‐operation NCX activity. A combination of NMDA and ouabain produced more rapid Ca2+overload, that was contributed to by NCX activity. These results suggest that degenerative Ca2+signaling can be triggered by NMDA in dendrites, before intracellular Na+levels become sufficient to reverse NCX activity. However, since Na+/K+ATPase inhibition does appear to produce significant reverse‐operation NCX activity, this additional Ca2+influx pathway may operate in ATP‐deprived CA1 neurons and play a role in ischemic neurodegeneration.

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