Hyperactivity,startle reactivity and cell‐proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1frc/frc mice

The NR2E1 region on Chromosome 6q21‐22 has been repeatedly linked to bipolar disorder (BP) and NR2E1 has been associated with BP, and more specifically bipolar I disorder (BPI). In addition, patient sequencing has shown an enrichment of rare candidate‐regulatory variants. Interestingly, mice carrying either spontaneous (Nr2e1^frc) or targeted (Tlx^?) deletions of Nr2e1 (here collectively known as Nr2e1‐null) show similar neurological and behavioral anomalies, including hypoplasia of the cerebrum, reduced neural stem cell proliferation, extreme aggression and deficits in fear conditioning; these are the traits that have been observed in some patients with BP. Thus, NR2E1 is a positional and functional candidate for a role in BP. However, no Nr2e1‐null mice have been fully evaluated for behaviors used to model BP in rodents or pharmacological responses to drugs effective in treating BP symptoms. In this study we examine Nr2e1^frc/frc mice, homozygous for the spontaneous deletion, for abnormalities in activity, learning and information processing, and cell proliferation; these are the phenotypes that are either affected in patients with BP or commonly assessed in rodent models of BP. The effect of lithium, a drug used to treat BP, was also evaluated for its ability to attenuate Nr2e1^frc/frc behavioral and neural stem cell‐proliferation phenotypes. We show for the first time that Nr2e1‐null mice exhibit extreme hyperactivity in the open field as early as postnatal day 18 and in the home cage, deficits in open‐field habituation and passive avoidance, and surprisingly, an absence of acoustic startle. We observed a reduction in neural stem/progenitor cell proliferation in Nr2e1^frc/frc mice, similar to that seen in other Nr2e1‐null strains. These behavioral and cell‐proliferation phenotypes were resistant to chronic‐adult‐lithium treatment. Thus, Nr2e1^frc/frc mice exhibit behavioral traits used to model BP in rodents, but our results do not support Nr2e1^frc/frc mice as pharmacological models for BP.