Reduced activity of the prefrontal cortex (PFC) is seen in mood disorders including depression and anxiety. The mechanisms of this hypofrontality remain unclear. Because of their specific physiological properties, parvalbumin-expressing (PV+) inhibitory interneurons contribute to the overall activity of the PFC. Our recent work using a chronic stress mouse model showed that stress-induced increases in prefrontal PV expression correlates with increased anxiety-like behaviors in female mice. Our goal is now to provide a causal relationship between changes in prefrontal PV+ cells and changes in emotional behaviors in mice. We first show that, in addition to increasing overall level of PV expression, chronic stress increases the activity of prefrontal PV+ cells. We then used a chemogenetic approach to mimic the effects of chronic stress and specifically increase the activity of prefrontal PV+ cells. We observed that chemogenetic activation of PV+ cells caused an overall reduction in prefrontal activity, and that chronic activation of PV+ cells lead to increased anxiety-related behaviors in female mice only. These results demonstrate that activity of prefrontal PV+ cells could represent a novel sex-specific modulator of anxiety-related behaviors, potentially through changes in overall prefrontal activity. The findings also support the idea that prefrontal PV+ cells are worth further investigation to better understand mood disorders that are more prevalent in female populations.

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Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia have an expansive array of reported genetic and environmental contributing factors. However, none of these factors alone can account for a substantial proportion of cases of either disorder. Instead, many gene-by-environment interactions are responsible for neurodevelopmental disturbances that lead to these disorders. The current experiment used heterozygous knock-out mice to examine a potential interaction between 2 factors commonly linked to neurodevelopmental disorders and cognitive deficit: imbalanced excitatory/inhibitory signaling in the cortex and prenatal stress (PNS) exposure. Both of these factors have been linked to disrupt GABAergic signaling in the prefrontal cortex (PFC), a common feature of neurodevelopmental disorders. The neuronal PAS domain protein 4 (Npas4) gene is instrumental in regulation of the excitatory/inhibitory balance in the cortex and hippocampus in response to activation. Npas4 heterozygous and wild-type male and female mice were exposed to either PNS or standard gestation, then evaluated during adulthood in social and anxiety behavioral measures. The combination of PNS and Npas4 deficiency in male mice impaired social recognition. This behavioral deficit was associated with decreased parvalbumin and cFos protein expression in the infralimbic region of the PFC following social stimulation in Npas4 heterozygous males. In contrast, females displayed fewer behavioral effects and molecular changes in PFC in response to PNS and decreased Npas4.

Dysfunction of prefrontal parvalbumin (PV+) interneurons has been linked with severe cognitive deficits as observed in several neurodevelopmental disorders including schizophrenia. However, whether a specific aspect of PV+ neurons deregulation, or a specific molecular mechanism within PV+ neurons is responsible for cognitive deficits and other behavioral impairments remain to be determined. Here, we induced cognitive deficits and altered the prefrontal PV system in mice by exposing them neonatally to the NMDA receptor antagonist ketamine. We observed that the cognitive deficits and hyperactivity induced by neonatal ketamine were associated with a downregulation of Npas4 expression specifically in PV+ neurons. To determine whether Npas4 downregulation-induced dysfunction of PV+ neurons could be a molecular contributor to the cognitive and behavioral impairments reported after neonatal ketamine, we used a transgenic Cre-Lox approach. Reduced Npas4 expression within PV+ neurons replicates deficits in short-term memory observed after neonatal ketamine, but does not reproduce disturbances in general activity. Our data show for the first time that the brain-specific transcription factor Npas4 may be an important contributor to PV+ neurons dysfunction in neurodevelopmental disorders, and thereby could contribute to the cognitive deficits observed in diseases characterized by abnormal functioning of PV+ neurons such as schizophrenia. These findings provide a potential novel therapeutic target to rescue the cognitive impairments of schizophrenia that remain to date unresponsive to treatments.