P1.17. IDENTIFICATION OF A NOVEL GENETIC MOUSE MODEL OF BIPOLAR DISORDER REVEALING SEX DIFFERENCES
Anthony Kischel1, Joanna Krzemień2, Joanna Sadlak-Buda1, Przemysław Duda1, Iana Garmash1, Ila Joshi1, Katarzyna Rojek2, Przemysław Kaczor1, Martyna Jakubas1, Magdalena Myrcha1, Paweł Boguszewski2, Lars Holmgren3, Tomasz J. Prószyński1
1 Łukasiewicz Research Network — PORT Polish Center for Technology Development, 147 Stabłowicka Street, 54-066 Wrocław, Poland.
2 Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland.
3 Karolinska institutet, Department of Oncology-Pathology, Bioclinicum, Stockholm 17164, Sweden.
INTRODUCTION: Bipolar disorder is a complex neuropsychiatric condition characterized by alternating manic and depressive episodes. While existing animal models capture certain mania-like symptoms, the precise mechanisms underlying the disorder remain poorly understood.
AIM(S): Developing more accurate models is therefore essential for advancing our understanding of its pathophysiology.
METHOD(S): In this study, using multilevel approaches from molecular to behavioral characterization, we introduce a novel genetic mouse model of bipolar disorder.
RESULTS: Male knockout (KO) mice exhibited hallmark features of mania, including locomotor hyperactivity, increased risk-taking behavior, heightened sensitivity to low-dose d-amphetamine, excessive circling and turning, and episodes of backward walking. These behavioral abnormalities were consistently observed in two complementary neuron-specific conditional KO lines. Additionally, KO mice displayed dysregulated dopamine and serotonin levels across multiple brain regions, along with evidence of impaired glutamatergic transmission.
Interestingly, female KO mice did not exhibit the same behavioral abnormalities as males. Instead, they showed increased anxiety-like behaviors and passive coping strategies, suggesting a sex-dependent divergence in phenotype, where males primarily exhibit mania-like traits while females display depressive-like features.
CONCLUSIONS: By closely recapitulating key aspects of bipolar disorder —including its sex-specific manifestations— this novel model represents a valuable tool for investigating the neurobiological mechanisms underlying the disorder. Furthermore, it offers a robust platform for testing potential therapeutic interventions.
FINANCIAL SUPPORT: Work supported by the Polish National Science Centre, NCN grant 2019/33/B/NZ3/02528.