The medial prefrontal cortex (mPFC) plays a critical role in complex brain functions including decision-making, integration of emotional, and cognitive aspects in memory processing and memory consolidation. Because relatively little is known about the molecular mechanisms underlying its development, we quantified rat mPFC basal expression levels of sets of plasticity, synaptic, glia, and connectivity proteins at different developmental ages. Specifically, we compared the mPFC of rats at postnatal day 17 (PN17), when they are still unable to express long-term contextual and spatial memories, to rat mPFC at PN24, when they have acquired the ability of long-term memory expression and finally to the mPFC of adult rats. We found that, with increased age, there are remarkable and significant decreases in markers of cell activation and significant increases in proteins that mark synaptogenesis and synapse maturation. Furthermore, we found significant changes in structural markers over the ages, suggesting that structural connectivity of the mPFC increases over time. Finally, the substantial biological difference in mPFC at different ages suggest caution in extrapolating conclusions from brain plasticity studies conducted at different developmental stages.