Depression is one of the prevalent psychiatric illnesses with a comprehensive performance such as low self-esteem, lack of motivation, anhedonia, poor appetite, low energy, and uncomfortableness without a specific cause. So far, the cause of depression is not very clear, but it is certain that many aspects of biological psychological and social environment are involved in the pathogenesis of depression. Recently, the prefrontal cortex (PFC) has been indicated to be a pivotal brain region in the pathogenesis of depression. And increasing evidence showed that the abnormal activity of the PFC neurons is linked with depressive symptoms. Unveiling the molecular and cellular, as well as the circuit properties of the PFC neurons will help to find out how abnormalities in PFC neuronal activity are associated with depressive disorders. In addition, concerning many antidepressant drugs, in this review, we concluded the effect of several antidepressants on PFC neuronal activity to better understand its association with depression.