Altered GluA1 ( Gria1 ) Function and Accumbal Synaptic Plasticity in the Clock Δ19 Model of Bipolar Mania

摘要

BackgroundDisruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood. MethodsUsing ex?vivo whole-cell patch-clamp electrophysiology inClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression ofGria1in the NAc and behavioral assays were also used. ResultsCompared with wild-type mice,ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor–mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased inClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential ofClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functionalGria1in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state. ConclusionsTogether, our findings demonstrate that NAc excitatory signaling viaGria1expression is integral to the effects ofClockgene disruption on manic-like behaviors.