Aberrant Cortical Activity in Multiple GCaMP6-Expressing Transgenic Mouse Lines

Abstract

Transgenic mouse lines are invaluable tools for neuroscience but as with any technique, care must be taken to ensure that the tool itself does not unduly affect the system under study. Here we report aberrant electrical activity, similar to interictal spikes, and accompanying fluorescence events in some genotypes of transgenic mice expressing GCaMP6 genetically-encoded calcium sensors. These epileptiform events have been observed particularly, but not exclusively, in mice with Emx1-Cre and Ai93 transgenes, of either sex, across multiple laboratories. The events occur at >0.1 Hz, are very large in amplitude (>1.0 mV local field potentials, >10% df/f widefield imaging signals), and typically cover large regions of cortex. Many properties of neuronal responses and behavior seem normal despite these events, though rare subjects exhibit overt generalized seizures. The underlying mechanisms of this phenomenon remain unclear, but we speculate about possible causes on the basis of diverse observations. We encourage researchers to be aware of these activity patterns while interpreting neuronal recordings from affected mouse lines and when considering which lines to study.

Significance Statement Genetically-encoded calcium sensors have revolutionized neuroscience by providing a powerful way to measure neural activity with optical imaging. Transgenic mice that express these indicators have proved a particularly useful technology for their stability, ease of use, and breadth of expression. However, here we report that some of these mouse lines have major abnormalities in their brain activity, including large, broad events resembling epileptic activity. We confirmed these abnormalities across multiple laboratories and we provide methods to detect them. This finding is an important point of caution for researchers using genetically-encoded calcium indicators to study neural activity.