THE ROLE OF PSA-NCAM IN THE THALAMIC RETICULAR NUCLEUS: IMPLICATIONS FOR INHIBITORY CIRCUITS AND THE IMPACT OF EARLY-LIFE STRESS

Exposure to early-life stress can profoundly affect brain development and behavior, increasing vulnerability to mental disorders. Both clinical and animal studies indicate that early adversity impacts parvalbumin (PV)-expressing interneurons, a key cell type implicated in these conditions. PV+ neurons undergo a prolonged maturation period during early postnatal life, which may render them especially sensitive to stress. This is particularly relevant for the thalamic reticular nucleus (TRN), a predominantly GABAergic structure in which many neurons express PV and contribute to thalamocortical regulation and sensorimotor gating. PV+ neuron maturation are shaped by extracellular matrix components and plasticity-related molecules, including polysialylated neural cell adhesion molecule (PSA-NCAM). PSA-NCAM regulates neurodevelopment and adult inhibitory circuit connectivity, yet its expression in the thalamus and its contribution to TRN organization remain poorly understood. Here, we characterized PSA-NCAM in the TRN across postnatal development and adulthood, examined its spatial relationship with PV+ neurons, synaptic markers, and perineuronal nets (PNNs), and tested its role in TRN-dependent function. We enzymatically depleted PSA from NCAM specifically in the TRN and assessed behavioral and electrophysiological consequences. PSA depletion produced behavioral alterations consistent with disrupted sensory gating and population-level electrophysiological changes suggesting distinct stimulus-evoked responses in the dorsal TRN. These effects were accompanied by increased NMDA receptor expression on PV+ neurons and increased PNN-related measures. Finally, we found that postweaning social isolation increased PSA-NCAM expression in the dorsal TRN, indicating that early-life stress modulates its regulation. Together, these findings identify PSA-NCAM as a stress-sensitive regulator of inhibitory circuit function in the TRN.