Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania

• Published in: The Journal of neuroscience Vol. 30; no. 48; pp. 16314 - 16323
• Main Authors: Dzirasa, Kafui, Coque, Laurent, Sidor, Michelle M, Kumar, Sunil, Dancy, Elizabeth A, Takahashi, Joseph S, McClung, Colleen A, Nicolelis, Miguel A L
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 01-12-2010
• Subjects: Animals; Biological Clocks - drug effects; Biological Clocks - physiology; Bipolar Disorder - drug therapy; Bipolar Disorder - genetics; Bipolar Disorder - physiopathology; Circadian Rhythm - drug effects; Circadian Rhythm - physiology; CLOCK Proteins - genetics; Disease Models, Animal; Lithium - pharmacology; Lithium - therapeutic use; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net - drug effects; Nerve Net - physiology; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiopathology; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.4289-10.2010

Polymorphisms in circadian genes such as CLOCK convey risk for bipolar disorder. While studies have begun to elucidate the molecular mechanism whereby disruption of Clock alters cellular function within mesolimbic brain regions, little remains known about how these changes alter gross neural circuit function and generate mania-like behaviors in Clock-Δ19 mice. Here we show that the phasic entrainment of nucleus accumbens (NAC) low-gamma (30-55 Hz) oscillations to delta (1-4 Hz) oscillations is negatively correlated with the extent to which wild-type (WT) mice explore a novel environment. Clock-Δ19 mice, which display hyperactivity in the novel environment, exhibit profound deficits in low-gamma and NAC single-neuron phase coupling. We also demonstrate that NAC neurons in Clock-Δ19 mice display complex changes in dendritic morphology and reduced GluR1 expression compared to those observed in WT littermates. Chronic lithium treatment ameliorated several of these neurophysiological deficits and suppressed exploratory drive in the mutants. These results demonstrate that disruptions of Clock gene function are sufficient to promote alterations in NAC microcircuits, and raise the hypothesis that dysfunctional NAC phase signaling may contribute to the mania-like behavioral manifestations that result from diminished circadian gene function.