Mapping nonapoptotic caspase activity with a transgenic reporter in mice

The protease caspase-3 is a key mediator of programmed cell death, or apoptosis. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no simple method for mapping and quantifying nonapoptotic caspase activity in rodent brains. We therefore generated a transgenic mouse expressing a highly sensitive and specific fluorescent reporter of caspase activity, with peak signal localized to the nucleus. Surprisingly, nonapoptotic caspase activity was prevalent in healthy adult brains and influenced neuronal functional connectivity. We quantified the relationship between caspase activity and cell firing and morphology. We also notably observed a sex-specific persistent elevation in amygdalar caspase activity in females after restraint stress. This simple in vivo caspase activity reporter will facilitate systems-level studies of apoptotic and nonapoptotic phenomena in behavioral and pathological models.