Npas4 deficiency increases vulnerability to juvenile stress in mice

•Npas4 deficient mice show long-term cognitive deficits after exposure to juvenile chronic stress.•Juvenile chronic stress induces long-lasting reduction of Npas4 expression in the prefrontal cortex.•Juvenile chronic stress reduces the number of migrating neuroblasts toward cortical regions in Npas-deficient mice.

During specific windows of postnatal brain development, individuals are particularly susceptible to developing mental illnesses in adulthood. Adolescence is such a window during which environmental stress can have long-lasting consequences on social and cognitive functions. In individuals, highly vulnerable to stress, a relatively mild stressful situation can trigger the onset of psychiatric conditions. The genetic factors and mechanisms underlying vulnerability to stress are not well understood. Here, we show that variations in expression of the brain-specific transcription factor Npas4 contributes to the long-term consequences of juvenile stress on cognitive abilities. We observed that transgenic Npas4-deficient mice exposed to chronic mild stress during adolescence (but not during adulthood) develop prefrontal cortex-dependent cognitive deficits in adulthood, while the same stress did not affect Npas4 wild-type mice. These cognitive deficits were accompanied by fewer neuroblasts in the subventricular zone, and reduced ability of these immature neuronal cells to migrate away from this neurogenic zone toward cortical regions. These findings suggest for the first time that the transcription factor Npas4 could play a significant role in coping with juvenile stress. They also suggest that Npas4 could modulate resilience or vulnerability to stress by mediating the effects of stress on neurogenesis.