Partial rodent genetic models for bipolar disorder.

Bipolar disorder (BPD) is a complex clinical phenomenon. This episodic illness comprises at least four features/components: depression, mania, vulnerability to mood swings in euthymic BPD patients, and spontaneous cyclicity in at least some BPD patients. Currently, there is no rodent genetic model capable of encompassing the whole phenotype of BPD exists; however, recent genetic-behavioral studies have delineated partial models for some components of BPD, namely, depression, mania, and vulnerability or resilience to mood swings. p11 knockout (KO), vesicular monoamine transporter 2 (VMAT2) heterozygous KO, and neural cell adhesion molecule (NCAM) KO mice display anhedonia-like symptoms, and treatment with antidepressants rescues this anhedonia-related phenotype. Mutant CLOCK, glutamate receptor 6 (GluR6) KO, and extracellular signal-regulated kinase 1 (ERK1) KO mice exhibit mania-like behavioral clusters referred to as excessive behavioral excitement; at least some of the exhibited behaviors can be rescued through treatment with mood stabilizers or atypical antipsychotics. Neuronal glucocorticoid receptor (GR) overexpressing, B-cell lymphoma 2 (Bcl-2) heterozygous KO, and Bcl-2-associated athanogene (BAG1) heterozygous KO mice show vulnerability to mood swings. In contrast, neuronal BAG1 overexpressing mice display resilience to mood swings. These mutant mouse strains and the behavioral approaches used to characterize these strains offer an emerging set of research tools for the comprehensive understanding of various components of BPD, and the interrelation of these components at the molecular, cellular, and neuronal circuitry levels. These partial genetic models can also be used as complementary tools to augment other existing behavioral tests and paradigms in drug development for BPD.