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 perc...Continue Reading