Table 3.

Genetic mouse models of bipolar mania

	Validity
Manipulation	Face	Predictive	Construct
ClockΔ19 mutant	Reduced anxiety, depression; increased impulsivity, reward-seeking; hyperactivity; impaired decision-making, sensorimotor gating; disrupted circadian rhythms (phase and amplitude) and sleep; episodic mania (mania and euthymia)	Lithium and valproic acid normalized anxiety and depression behavior. Lithium normalized dopaminergic activity and defects in cross frequency phase coupling in the NAc.	CLOCK polymorphisms; disrupted phase coherence, synchronization, and communication of cortico-striatal circuitry; hyperdopaminergia and altered glutamatergic neurotransmission
GSK-3β OX	Hyperactivity; reduced depression	Lithium reduced activity	GSK-3β polymorphisms; reduced expression human bipolar DLPFC and temporal cortex; disrupted downstream targets of GSK-3β (e.g., β-catenin); hyperdopaminergia
DAT-KD	Hyperactivity (reduced spatial d); increased goal-directed behavior; repetitive locomotor patterns; impaired decision-making	Valproic acid reduced hyperactivity	DAT polymorphisms; impaired DAT function; hyperdopaminergia
SHANK3-OX	Hyperactivity; hypersensitivity to reward stimuli (e.g., amphetamine); elevated acoustic startle response; impaired sensorimotor gating; reduced depression; altered circadian rhythm behavior	No effect of lithium; valproic acid reduced hyperactivity, amphetamine-induced locomotion, normalized sensorimotor deficits; reversed abnormal EEG patterns in frontal cortex and hippocampus	SHANK3 polymorphisms; variants predict treatment response to ketamine in patients with bipolar depression; imbalance between excitatory and inhibitory neurotransmission; altered dopaminergic and glutamatergic signaling
ANK3 disruptions	Hyperactivity; reduced anxiety; altered circadian activity rhythms; increased reward-seeking; stress-induced anxiety, anhedonia	Lithium reduced hyperactivity, normalized anxiety	Potential regulation of β-catenin and Wnt signaling pathways
GCLM-KO	Hypersensitivity to amphetamine locomotor effects; altered social behavior; impaired sensorimotor gating	Untested	Reduced GSH levels in human postmortem PFC and other brain regions from bipolar patients; GSH alterations associated with GABA dysfunction, oxidative stress markers, and altered dopaminergic neurotransmission
Myshkin mutant	Hyperactivity; hypersensitivity to amphetamine locomotor effects; impaired sensorimotor gating; disrupted sleep homeostasis; altered circadian rhythm behavior	Lithium or valproic acid normalized anxiety and hyperactivity; exercise and melatonin improved sleep quality, reduced hyperactivity and normalized anxiety	ATP1A3 polymorphisms, NA+K+ATPase a3 sodium pump dysfunction, multiple isoforms associated with bipolar disorder; altered ERK signaling and downstream effectors, such as BDNF, DISC1, GluR6, RASGRP1, and EGFR
Black Swiss	Hyperactivity; hypersensitivity to amphetamine locomotor effects; reduced anxiety and depression; elevated sucrose preference	Lithium and valproic acid reduced sucrose preference, amphetamine-induced locomotion, normalized depression behavior; asenapine (antipsychotic) normalized depression, reduced hyperactivity and amphetamine induced activity	Genetic heterogeneity; reduced β-catenin expression in various brain regions
Madison	Hyperactivity; reduced anxiety and depression; increased sexual behavior; disrupted circadian rhythm behaviors	Lithium and olanzapine selectively reduced hyperactivity	Genetic heterogeneity; abnormal expression patterns of numerous genes associated with bipolar disorder (e.g., Smarca4)
DBP-KO	Abnormal circadian rhythm behaviors; disrupted sleep homeostasis; reduced activity; mania-like behaviors induced by chronic stress or acute sleep deprivation include hyperactivity, increased drug-taking	Valproic acid blocked stress-induced hyperactivity	Gene locus mapped near coding region for Dbp; ranked highly among candidate genes for bipolar disorder