The transcription factor Npas4 contributes to adolescent development of prefrontal inhibitory circuits, and to cognitive and emotional functions: Implications for neuropsychiatric disorders

- Npas4 is highly expressed in the adolescent prefrontal cortex (PFC).
- Adolescent Npas4 deficient mice display sex-specific abnormalities in GABA transmission.
- Adolescent deletion of Npas4 leads to sex-specific cognitive and emotional deficits.
- Adolescent pharmacological enhancement of GABA transmission rescues behavioral deficits.

The adolescent brain is marked by functional and structural modifications, particularly within the inhibitory system of the prefrontal cortex (PFC). These changes are necessary for the acquisition of adult cognitive functions and emotion regulation, and impairments in these processes are associated with neuropathologies such as schizophrenia and affective disorders. The molecular mechanisms regulating this adolescent refinement of prefrontal inhibitory circuits remain largely unknown. Here we demonstrate that the transcription factor Npas4 plays a major role in this process. Using a series of behavioral, molecular, pharmacological and genetic approaches in mice, we demonstrate that deficiency in Npas4 affects adolescent expression of multiple markers of GABAergic transmission in the PFC, including parvalbumin and GAD67, in a sex-specific manner. This abnormal pattern of expression of GABAergic markers is associated with sex-specific cognitive and emotional impairments that occur only when Npas4 deficiency begins at adolescence but not post-adolescence. Finally, we show that chronic treatment with the GABA enhancing drug sodium valproate during adolescence is sufficient to induce long-lasting recovery of the molecular and behavioral abnormalities observed in Npas4 deficient mice. Altogether, we provide evidence for the involvement of the transcription factor Npas4 to the structural changes that affect prefrontal inhibitory circuits during adolescence. Further investigations of Npas4 role in the adolescent brain might provide new insights on the molecular mechanisms underlying neuropsychiatric disorders that emerge during adolescence.