A study by Steinmetz et al. has shown that a number of transgenic mouse lines used for neuroscience research may develop abnormal brain activity resembling epileptic events. Specifically, some genotypes of transgenic mice expressing GCaMP6 genetically encoded calcium sensors exhibited aberrant electrical activity similar to interictal spikes, leading the authors to offer warning to other researchers using these lines.
Findings from this new study present a cause for concern for researchers as the presence of unusual brain activity can affect the validity of any neural investigation. The study was carried out across multiple laboratories and employed various neurological observations to detect unusual brain activity in transgenic mouse lines.
The researchers observed highly distinctive epileptiform events in various mouse lines, particularly in those expressing the Emx1-Cre and Ai93 transgenes. The events were described to cover large regions of the cortex but did not seem to affect the behavior of most of the mouse lines; although in rare cases, some of the mice exhibited seizures.
The neurological events found in the transgenic mouse lines were described as epileptic events due to the detection of interictal spikes typically observed in human epileptic patients. These interictal spikes are easily distinguishable and are often pathologic.
Researchers claim that these epileptic events may have been missed in the past by researchers because the mice rarely show any behavioral manifestation. Furthermore, the events are generally absent in the visual cortex, a commonly studied region of the brain.
The researchers are yet to uncover the underlying mechanisms of these epileptiform events but they have outlined some factors that may contribute to their occurrence. They theorize that the broad expression of GCaMP in the early stages of the mouse development could be a major factor.
The team observed that GCaMP expression relies heavily on the activity of tTA; a regulator of gene expression. When tTA activity was suppressed with doxycycline until 7 weeks of age in postnatal mice, the expression of GCaMP had also significantly decreased and there were no epileptic events observed. The epileptiform events, however, were detected in adulthood when the mice stopped receiving doxycycline treatment.
Ultimately, the findings from this study may prompt researchers to consider this aberrant activity when interpreting results from transgenic mice, in addition to wider consideration of alternative mouse lines and techniques.
Sources: Steinmetz NA, Buetfering C, Lecoq J et al. Aberrant cortical activity in multiple GCaMP6-expressing transgenic mouse lines. eNeuro 4(5), 0207–0217 (2017); www.eurekalert.org/pub_releases/2017-09/sfn-eba082917.php