Beta-Ca²⁺/calmodulin-dependent protein kinase II (βCaMKII) is known as a powerful regulator of lateral habenula neuron function and a key molecular determinant of depression. βCaMKII is also abundant in the hippocampus, especially in the dentate gyrus (DG). However, whether βCaMKII in the DG is also involved in emotional behaviors remains unknown. In this study, using βCaMKII-F90G transgenic mice, in which the overexpression of βCaMKII is restricted to the DG, we demonstrated that βCaMKII overexpression in the DG has no effect on the level of anxiety in mice in open field test or light–dark box test. Moreover, tail suspension test and forced swim test showed that the level of depression in βCaMKII-F90G transgenic mice and their littermates was comparable. Taken together, our findings indicate that βCaMKII overexpression in the DG does not result in depression- and anxiety-like behaviors in mice and provide evidence that the function of βCaMKII in emotional behaviors is brain region specific.

Post-traumatic stress disorder (PTSD) patients have severe fear extinction disorder, but the underlying molecular and neurobiological mechanisms are still unknown. The hippocampus has sub-regional specific functions, however, their involvement in PTSD is unclear. In this study, we used under water trauma (UWT) model rats which exhibit multiple core PTSD symptoms, including anxiety, depression, and impaired fear extinction. In the dorsal or ventral hippocampus, we found that long-term depression at Schaffer collateral and medial perforant pathway was impaired in UWT model rats. Moreover, although the expression levels of ionotropic glutamate receptors including NR2A, NR2B, GluA1, and GluA2 were normal, the activity of alpha calcium/calmodulin-dependent protein kinase II (αCaMKII) significantly increased in both the dorsal and ventral hippocampus of UWT model rats. These findings reveal similar abnormalities in synaptic plasticity and αCaMKII activity in different hippocampal sub-regions of UWT rats. Our results shed light on the region-specific role of the hippocampus in PTSD and provide a theoretical basis for the development of specific treatments for PTSD.

Major depressive disorder (MDD) is a recurring mental illness that has brought severe physical and psychological burdens to people around the world and caused heavy medical and economic burdens on society. For many years, the monoamine hypothesis based on the first- and second-generation antidepressants have been developed and put into clinical use, but the traditional monoamine antidepressants have a series of problems, such as poor targeting, strong side effects, and slow onset. The emergence of non-monoamine antidepressants such as ketamine, scopolamine, and brexanolone has injected new impetus into the development of long-silent antidepressants. They have the characteristics of fast onset, low toxicity, fewer side effects, and a better response rate to treatment-resistant depression (TRD). This review will discuss the characteristics, mechanisms, advantages, and remaining problems of non-monoamine antidepressants, and provide recommendations for future clinical and scientific research.