Interictal spikes during spatial working memory carry helpful or distracting representations of space and have opposing impacts on performance.
In temporal lobe epilepsy, interictal spikes (IS) - hypersynchronous bursts of network activity - occur at high rates in between seizures. We sought to understand the influence of IS on working memory by recording hippocampal local field potentials from epileptic mice while they performed a delayed alternation task. We found that IS disrupted performance when they were spatially non-restricted and occurred during running. In contrast, when IS were clustered at reward locations, animals performed well. A machine learning decoding approach revealed that IS at reward sites were larger than IS elsewhere on the maze, and could be classified as occurring at specific reward locations - suggesting they carry informative content for the memory task. Finally, a spiking model revealed that spatially clustered IS preserved hippocampal replay, while spatially dispersed IS disrupted replay by causing over-generalization. Together, these results show that IS can have opposing outcomes on memory.