Dysregulation of the mesoprefrontal dopamine circuit mediates an early-life stress-induced synaptic imbalance in the prefrontal cortex

Summary: Stress adversely affects an array of cognitive functions. Although stress-related disorders are often addressed in adulthood, far less is known about how early-life stress (ELS) affects the developing brain in early postnatal periods. Here we show that ELS, induced by maternal separation, leads to synaptic alteration of layer 2/3 pyramidal neurons in the prefrontal cortex (PFC) of mice. We find that layer 2/3 neurons show increased excitatory synapse numbers following ELS and that this is accompanied by hyperexcitability of PFC-projecting dopamine (DA) neurons in the ventral tegmental area. Notably, excitatory synaptic change requires local signaling through DA D2 receptors. In vivo pharmacological treatment with a D2 receptor agonist in the PFC of control mice mimics the effects of ELS on synaptic alterations. Our findings reveal a neuromodulatory mechanism underlying ELS-induced PFC dysfunction, and this mechanism may facilitate a more comprehensive understanding of how ELS leads to mental disorders.