Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania.
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.
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA. dzira001@mc.duke.edu
Kafui
K
Dzirasa
Laurent
L
Coque
Michelle M
MM
Sidor
Sunil
S
Kumar
Elizabeth A
EA
Dancy
Joseph S
JS
Takahashi
Colleen A
CA
McClung
Miguel A L
MA
Nicolelis
D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D056926:CLOCK Proteins / Q000235:genetics*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D008094:Lithium; D056926:CLOCK Proteins; C538944:Clock protein, mouse