Environmental enrichment modulates parvalbumin interneuron deficits and plasticity-related signaling after early postnatal NMDA receptor hypofunction in male rat visual cortex

Abstract

Abstract Sensory processing deficits in schizophrenia have been linked to dysfunction of cortical inhibitory interneurons, particularly parvalbumin-expressing (PV+) populations. NMDA receptor hypofunction during development is known to disrupt interneuron maturation, but its long-term impact on visual cortex circuitry and the potential for experience-dependent modulation in adulthood remain unclear. Here, we examined the effects of early postnatal N-methyl-D-aspartate (NMDA) receptor blockade with MK-801 on the number of PV+ and somatostatin-expressing (SST+) interneurons in the primary visual cortex (V1) and assessed whether environmental enrichment (EE) in adulthood modulates these alterations by analyzing molecular changes using Western blot. Male Long–Evans rats received MK-801 (0.5 mg/kg) or saline from postnatal day 10–20, followed by EE exposure from P55–73. Stereological analyses revealed a marked reduction of PV-immunoreactive cells in layers II/III and IV, while SST+ populations were largely preserved. EE increased the number of PV-immunoreactive cells across groups, and modestly enhanced SST+ cells in layer IV, although no treatment × housing interaction was detected, indicating a general enrichment-related effect. At the molecular level, MK-801 reduced expression of the NMDA receptor subunit NR1 and increased Akt phosphorylation, whereas EE enhanced PSD95 expression, ERK phosphorylation, and GABA A β2/3 subunit levels, without increasing NR1 levels. These findings indicate that early NMDA receptor hypofunction induces long-lasting, subtype-specific alterations in inhibitory circuitry in V1. EE in adulthood engages molecular pathways associated with synaptic plasticity and modulates interneuron immunoreactivity, suggesting that inhibitory circuits retain some capacity for experience-dependent remodeling despite persistent receptor-level deficits.