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The cellular underpinnings of memory deficits in Alzheimer’s disease (AD) are poorly understood. We utilized the tractable neural circuits sub-serving memory in  Drosophila  to investigate the role of impaired Ca 2+  handling in memory deficits caused by expression of human 0N4R isoform of tau which is associated with AD. Expression of tau in mushroom body neuropils, or a subset of mushroom body output neurons, led to impaired memory. By using the Ca 2+  reporter GCaMP6f, we observed changes in Ca 2+  signaling when tau was expressed in these neurons, an effect that could be blocked by the L-type Ca 2+  channel antagonist nimodipine or reversed by  RNAi  knock-down of the L-type channel gene. The L-type Ca 2+  channel itself is required for memory formation, however,  RNAi  knock-down of the L-type Ca 2+  channel in neurons overexpressing human tau resulted in flies whose memory is restored to levels equivalent to wild-type. Expression data suggest that  Drosophila  L-type Ca 2+  channel mRNA levels are increased upon tau expression in neurons, thus contributing to the effects observed on memory and intracellular Ca 2+  homeostasis. Together, our Ca 2+  imaging and memory experiments suggest that expression of the 0N4R isoform of human tau increases the number of L-type Ca 2+  channels in the membrane resulting in changes in neuronal excitability that can be ameliorated by  RNAi  knockdown or pharmacological blockade of L-type Ca 2+  channels. This highlights a role for L-type Ca 2+  channels in tauopathy and their potential as a therapeutic target for AD.

Restoration of Olfactory Memory in Drosophila Overexpressing Human Alzheimer’s Disease Associated Tau by Manipulation of L-Type Ca2+ Channels