title: Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1(frc/frc) mice.
abstract: 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics at the Child & Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: B K Y
authors.initials: BK
authors.lastname: Wong
authors.forename: S M
authors.initials: SM
authors.lastname: Hossain
authors.forename: E
authors.initials: E
authors.lastname: Trinh
authors.forename: G A
authors.initials: GA
authors.lastname: Ottmann
authors.forename: S
authors.initials: S
authors.lastname: Budaghzadeh
authors.forename: Q Y
authors.initials: QY
authors.lastname: Zheng
authors.forename: E M
authors.initials: EM
authors.lastname: Simpson
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D004435:Eating / Q000187:drug effects / Q000235:genetics; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D005838:Genotype; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000235:genetics; D019417:Hindlimb Suspension / Q000523:psychology; D006358:Hot Temperature; D006948:Hyperkinesis / Q000188:drug therapy* / Q000235:genetics*; D007150:Immunohistochemistry; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018692:Antimanic Agents; C490258:Nr2e1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018021:Lithium Chloride