Maladaptive Neuroplasticity Under Stress: Insights into Neuronal and Synaptic Changes in the Prefrontal Cortex

Chronic stress can lead to maladaptive neuroplastic changes in the brain, with the prefrontal cortex (PFC) being a critical site of vulnerability due to its role in executive function and emotional regulation. Extensive evidence has confirmed that chronic stress induces neuroplasticity changes at multiple scales, including functional reorganization, intrinsic neuronal excitability, and structural and synaptic plasticity. These alterations are particularly prominent in glutamatergic pyramidal neurons of the PFC and involve synaptic weakening, dendritic retraction, spine loss, and impaired long-term potentiation. The paradoxical findings regarding pyramidal neuron excitability-ranging from hyper- to hypoactivity-highlight the complex and dynamic nature of stress-induced plasticity. One proposed mechanism linking these alterations is excitotoxicity, characterized by excessive glutamate signaling, impaired astrocytic clearance, and calcium overload, ultimately leading to synaptic dysfunction and structural degeneration. Additionally, inhibitory interneurons and glial cells might also play essential roles in shaping and modulating the stress response. This review integrates findings across neuroplasticity levels to provide a comprehensive understanding of how chronic stress reshapes the PFC. We further discuss the therapeutic potential of targeting homeostatic plasticity as a compensatory mechanism and propose future directions to clarify temporal dynamics, circuit specificity, and molecular regulators underlying maladaptive neuroplasticity in stress-related disorders.