Chronic stress-related behavioral and synaptic changes require caspase-3 activation in the ventral hippocampus of male mice.

Although numerous studies have suggested that chronic stress is a major risk factor for major depressive disorder, the process by which stress causes depression is still not fully understood. Previously, we investigated glucocorticoids, which are stress response hormones that activate a synapse-weakening pathway. Therefore, we hypothesized that chronic stress may cause synaptic depression, which could reduce excitability related to emotions. Animals underwent chronic restraint stress (CRS), followed by basal synaptic transmission measurement in hippocampal slices to assess synaptic function. Drugs were infused into the ventral hippocampus via cannulation before behavioral tests, including forced swimming, tail suspension, and sucrose intake tests, which evaluated depressive-like behaviors and anhedonia. The field excitatory postsynaptic potentials (fEPSPs) are reduced by chronic restraint stress (CRS) in the ventral hippocampus. The ventral hippocampi of mice treated with CRS showed low levels of fEPSP after the forced swim test (FST). In the FST and tail suspension test, CRS-induced increases in immobility time were prevented by the acute inhibition of AMPAR internalization by Tat-GluA2, which also prevented fEPSP reduction. Mice lacking caspase-3 exhibited resilience to CRS-induced increases in immobility time in the FST, as well as changes in the functionality of synaptic AMPAR. Finally, the caspase-3 inhibitor Z-DEVD-FMK rapidly blocked the CRS-induced increase in immobility time in the FST and the CRS-induced decrease in sucrose preference. These findings suggest that chronic stress-related behavioral changes may require caspase-3-dependent alterations in ventral hippocampal synapses.