Stress induces insertion of calcium-permeable AMPA receptors in the OFC\u2013BLA synapse and modulates emotional behaviours in mice

Abstract

Stress increases the risk of neuropsychiatric disorders, such as major depression. Exposure to stress has been reported to induce various neuronal changes, such as alterations in synaptic transmission and structure. However, a causal link between stress-induced neural circuit alterations and changes in emotional behaviours is not well understood. In the present study, we focused on a projection pathway from the orbitofrontal cortex (OFC) to the basolateral nucleus of the amygdala (BLA) as a crucial circuit for negative emotions and examined the effect of stress on OFC–BLA excitatory synaptic transmission using optogenetic and whole-cell patch-clamp methods in mice. As a stress-inducing procedure, we used repeated tail-shock, which increased stress-related behaviours. We found greater α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-d-aspartate current ratios and insertion of calcium-permeable AMPA receptors (AMPARs) in the OFC–BLA synapse after stress. These stress-induced synaptic and behavioural changes were reduced by a blockade of protein kinase A, which plays a principal role in stress-induced targeting of AMPARs into the synaptic membrane. To examine a possible causal relationship between alterations in synaptic transmission in the OFC–BLA pathway and stress-related behaviour, we performed optogenetic activation or chemogenetic inactivation of OFC–BLA transmission in mice. We found that optogenetic activation and chemogenetic inactivation of OFC–BLA transmission increased and decreased stress-related behaviour, respectively. In conclusion, we have demonstrated that stress altered the postsynaptic properties of the OFC–BLA pathway. These synaptic changes might be one of the underlying mechanisms of stress-induced behavioural alterations.