Parvalbumin interneurons under stress: converging mechanisms of vulnerability

From early life to adulthood, stress shapes brain circuits by impacting vulnerable neuron populations, with parvalbumin-expressing interneurons (PVIs) emerging as particularly sensitive targets. These fast-spiking interneurons orchestrate inhibitory control, maintain excitatory/inhibitory balance, and regulate network oscillations, all of which are crucial for cognitive and emotional function. In addition, PVIs play a central role in regulating stress vulnerability and resilience. Several cellular and molecular mechanisms have been implicated in stress-induced PVI deficits, including disrupted developmental trajectories, redox and metabolic vulnerabilities, inflammatory and microglia-associated signaling, and epigenetic modulation. Stress also remodels perineuronal nets (PNNs), specialized extracellular matrix structures that enwrap PVIs and contribute to their stabilization, the regulation of synaptic function, and protection against oxidative stress. This review synthesizes evidence from rodent models of stress, detailing putative mechanisms through which stress alters PVIs, their associated PNNs, and their circuit-level consequences across development and brain regions, including sex-dependent effects. It further discusses pharmacological and adjuvant interventions that may mitigate stress-induced PVI dysfunction, including monoaminergic modulators, ketamine and its derivatives, as well as anti-inflammatory and antioxidant strategies. By integrating mechanistic insights with potential strategies to protect or restore PVI function, we aim to provide a framework for understanding and reducing stress-induced psychiatric outcomes.