Down-Regulation of KV4 Channel in Drosophila Mushroom Body Neurons Contributes to Aβ42-Induced Courtship Memory Deficits.

Accumulation of amyloid-β (Aβ) is widely believed to be an early event in the pathogenesis of Alzheimer's disease (AD). Kv4 is an A-type K+ channel, and our previous report shows the degradation of Kv4, induced by the Aβ42 accumulation, may be a critical contributor to the hyperexcitability of neurons in a Drosophila AD model. Here, we used well-established courtship memory assay to investigate the contribution of the Kv4 channel to short-term memory (STM) deficits in the Aβ42-expressing AD model. We found that Aβ42 over-expression in Drosophila leads to age-dependent courtship STM loss, which can be also induced by driving acute Aβ42 expression post-developmentally. Interestingly, mutants with eliminated Kv4-mediated A-type K+ currents (IA) by transgenically expressing dominant-negative subunit (DNKv4) phenocopied Aβ42 flies in defective courtship STM. Kv4 channels in mushroom body (MB) and projection neurons (PNs) were found to be required for courtship STM. Furthermore, the STM phenotypes can be rescued, at least partially, by restoration of Kv4 expression in Aβ42 flies, indicating the STM deficits could be partially caused by Kv4 degradation. In addition, IA is significantly decreased in MB neurons (MBNs) but not in PNs, suggesting Kv4 degradation in MBNs, in particular, plays a critical role in courtship STM loss in Aβ42 flies. These data highlight causal relationship between region-specific Kv4 degradation and age-dependent learning decline in the AD model, and provide a mechanism for the disturbed cognitive function in AD.