Animal Models of Bipolar Disorder Mechanisms

Animal models of bipolar disorder employ genetic, pharmacological and environmental manipulations to reproduce mood-cycling, hyperactivity and depression-like states. Rodents lacking histidine triad nucleotide-binding protein 1 (HINT1), for example, exhibit alternating mania- and depression-like behaviour in response to stress, accompanied by dysregulated protein kinase C (PKC), glycogen synthase kinase 3β (GSK3β) and glutamate receptor signalling. Other approaches use pharmacological agents—amphetamine or ketamine—to induce mania-like phenotypes or mimic treatment-induced switches, while circadian or photoperiodic manipulations explore seasonal vulnerability. Validity is assessed through construct, face and predictive criteria, and outcomes inform molecular mechanisms, candidate drug targets and translational strategies.

Research from Nature Portfolio

Studies of HINT1-deficient mice have illuminated the molecular basis of behavioural cycling. Naïve HINT1 knockout animals display manic-like hyperactivity, elevated PKC, protein kinase A and GSK3β activities, and shifts in NR2B/NR2A NMDA receptor subunit ratios. Under stress these mice rapidly transition to depressive-like behaviours, which persist and can be reversed by selective inhibition of PKC or GSK3β, or by modulation of NMDA receptors. Such findings establish a robust platform for probing the switch mechanism between mood states and for testing novel mood-stabilising compounds.

Animal Models of Bipolar Disorder Mechanisms publication trend

The graph below shows the total number of articles in animal models of bipolar disorder mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Construct validity: Degree to which a model reproduces underlying biological mechanisms of a disorder.

Face validity: Extent to which model behaviours resemble clinical symptoms.

Predictive validity: Model’s responsiveness to therapeutics effective in human patients.

GSK3β: A serine–threonine kinase central to mood regulation and circadian rhythms.

NMDAR: N-methyl-D-aspartate receptor, a glutamate-gated ion channel mediating synaptic plasticity.

P2X7 receptor: A purinergic receptor involved in neuroinflammation and mood modulation.

References

1. Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature. Translational Psychiatry (2024).
2. P2X7 receptor inhibition alleviates mania-like behavior independently of interleukin-1β. iScience (2024).
3. Animal models for bipolar disorder: from bedside to the cage. International Journal of Bipolar Disorders (2017).
4. Enlightened: addressing circadian and seasonal changes in photoperiod in animal models of bipolar disorder. Translational Psychiatry (2021).
5. Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces. Scientific Reports (2017).
6. Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway. 动物学研究 (2022).