Npas4 deficiency interacts with adolescent stress to disrupt prefrontal GABAergic maturation and adult cognitive flexibility.

Healthy cognitive and emotional functioning relies on a balance between excitatory and inhibitory neurotransmission in the prefrontal cortex (PFC). This balance is largely established during early postnatal and adolescent developmental periods by maturation of the γ-aminobutyric acid (GABA) system, including increased density of parvalbumin (PV) cells and perineuronal nets (PNNs). Genetic and/or environmental factors during adolescence can disrupt GABAergic maturation and lead to behavioral dysfunction in adulthood. The present study examined the interaction between chronic mild stress during adolescence and genetic deficiency of neuronal Per-Arnt-Sim domain 4 (Npas4), a brain-specific transcription factor that regulates inhibitory neurotransmission and that contributes to adolescent prefrontal GABAergic maturation. Male Npas4 wild-type (WT) and heterozygous (HET) mice were exposed to adolescent chronic stress and tested in adulthood for cognitive function using the attention set shifting task. When Npas4 deficiency was combined with adolescent stress, mice displayed impaired cognitive flexibility as observed by poor performance on the extra-dimensional set shift task. At the cellular level, adolescent stress increased the percentage of PV cells surrounded by PNNs in the PFC of adult WT animals, an effect that was not observed in HET mice. Additionally, Npas4 deficiency and/or adolescent stress dysregulated expression of certain GABAergic system markers. These results suggest that Npas4 mediates susceptibility to adolescent stress and subsequent cognitive functioning and inhibitory tone in adulthood. This shows a novel gene by environment interaction related to resilience vs vulnerability to stress, with implications for adolescent onset disorders like schizophrenia.