Mania-like behavior induced by genetic dysfunction of the neuron-specific Na
            <sup>+</sup>
            ,K
            <sup>+</sup>
            -ATPase α3 sodium pump

Kirshenbaum, Greer S.; Clapcote, Steven J.; Duffy, Steven; Burgess, Christian R.; Petersen, J. W.; Jarowek, Karolina J.; Yücel, Yeni H.; Cortez, Miguel A.; Snead, O. Carter; Vilsen, Bente; Peever, John H.; Ralph, Martin R.; Roder, John

doi:10.1073/pnas.1108416108

Cited by 134 publications

(154 citation statements)

References 63 publications

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“…The sodium-potassium pump (Na-K-ATPase) controls membrane excitability by exchanging 3 Na ions for 2 K ions by hydrolysis of ATP [144]; dysregulation of Na-K-ATPase would alter the excitability of neurons along with the ATP/adenosine diphosphate balance. Transgenic mice with a mutation in Na-K-ATPase resulting in a reduced efficacy showed increased locomotion as well as reduced anxiety, exploratory behavior, and REM sleep latency behaviors similar to manic patients; cultured cortical neurons from these mutant mice also displayed increased calcium signaling [145]. An imbalance in ATP and myo-inositol shuttling would result in a change in energy production, metabolism, and expenditure.…”

Section: The Phenome Of Bd From the Ion Channel Perspectivementioning

confidence: 99%

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

2015

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Recent advances in genome-wide association studies are pointing towards a major role for voltage-gated ion channels in neuropsychiatric disorders and, in particular, bipolar disorder (BD). The phenotype of BD is complex, with symptoms during mood episodes and deficits persisting between episodes. We have tried to elucidate the common neurobiological mechanisms associated with ion channel signaling in order to provide a new perspective on the clinical symptoms and possible endophenotypes seen in BD patients. We propose a model in which the multiple variants in genes coding for ion channel proteins would perturb motivational circuits, synaptic plasticity, myelination, hypothalamic-pituitary-adrenal axis function, circadian neuronal rhythms, and energy regulation. These changes in neurobiological mechanisms would manifest in endophenotypes of aberrant reward processing, white matter hyperintensities, deficits in executive function, altered frontolimbic connectivity, increased amygdala activity, increased melatonin suppression, decreased REM latency, and aberrant myo-inositol/ATP shuttling. The endophenotypes result in behaviors of poor impulse control, motivational changes, cognitive deficits, abnormal stress response, sleep disturbances, and energy changes involving different neurobiological process domains. The hypothesis is that these disturbances start with altered neural circuitry during development, following which multiple environmental triggers may disrupt the neuronal excitability balance through an activity-dependent molecular process, resulting in clinical mood episodes.

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Section: The Phenome Of Bd From the Ion Channel Perspectivementioning

confidence: 99%

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

2015

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“…3 Myshkin mice carrying an inactivating mutation in the neuron-specific Na ϩ ,K ϩ -adenosine triphosphatase ␣3 subunit exhibit a behavioral profile similar to patients with bipolar disorder in the manic state. 4 Aside from being ameliorated by lithium and valproic acid, this mania-like phenotype was rescued by the transgenic expression of a functional Na ϩ ,K ϩ -adenosine triphosphatase ␣3 protein, which may be an important target for new antimanic therapies.…”

Section: Abstract Thinkingmentioning

confidence: 99%

In This Issue/Abstract Thinking: Of Mice, Monkeys, and Men

Singh

2012

Journal of the American Academy of Child & Adolescent Psych

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“…Interestingly, blocking the extracellular-regulated kinase (ERK) or treating with lithium rescued the manic behavior in these mice (Kirshenbaum, Clapcote et al 2011), implicating ERK signaling in lithium-mediated effects. A recent study has described signaling cross talk between ERK and GSK3β pathways in regulating GABAergic transmission via gephyrin phosphorylation at S268 and S270…”

Section: Introductionmentioning

confidence: 99%

Basic presynaptic functions in hippocampal neurons are not affected by acute or chronic lithium treatment

et al. 2013

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Lithium is an effective mood-stabilizer in the treatment of bipolar affective disorder. While glycogen synthase kinase 3-mediated and inositol depletion-dependent effects of lithium have been described extensively in literature, there is very little knowledge about the consequences of lithium treatment on vesicle recycling and neurotransmitter availability. In the present study we have examined acute and chronic effects of lithium on synaptic vesicle recycling using primary hippocampal neurons. We found that exocytosis of readily releasable pool vesicles as well as recycling pool vesicles was unaffected by acute and chronic treatment within the therapeutic range or at higher lithium concentrations. Consistent with this observation, we also noticed that the network activity and number of active synapses within the network were also not significantly altered after lithium treatment. Taken together, as lithium treatment does not affect synaptic vesicle release at even high concentrations, our data suggest that therapeutic effects of lithium in bipolar affective disorder are not directly related to presynaptic function. AbstractLithium is an effective mood-stabilizer in the treatment of bipolar affective disorders. While glycogen synthase kinase 3-mediated and inositol depletion-dependent effects of lithium have been described extensively in literature, there is very little knowledge about the consequences of lithium treatment on vesicle recycling and neurotransmitter availability. In the present study we have examined acute and chronic effects of lithium on synaptic vesicle recycling using primary hippocampal neurons. We found that exocytosis of readily releasable pool vesicles as well as recycling pool vesicles was unaffected by acute and chronic treatment within the therapeutic range or at higher lithium concentrations.Consistent with this observation, we also noticed that the network activity and number of active synapses within the network were also not significantly altered after lithium treatment. Taken together, as lithium treatment does not affect synaptic vesicle release at even high concentrations, our data suggest that therapeutic effects of lithium in bipolar affective disorder are not directly related to presynaptic function.

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Mania-like behavior induced by genetic dysfunction of the neuron-specific Na ⁺ ,K ⁺ -ATPase α3 sodium pump

Abstract: Endogenous period is extended in Myk/ + due to longer periods of (I) activity (α). All data are presented as means ± SEM, P < 0.05, P < 0.01; P < 0.001 compared with +/+ mice.

Cited by 134 publications

References 63 publications

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

In This Issue/Abstract Thinking: Of Mice, Monkeys, and Men

Basic presynaptic functions in hippocampal neurons are not affected by acute or chronic lithium treatment

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Mania-like behavior induced by genetic dysfunction of the neuron-specific Na + ,K + -ATPase α3 sodium pump

Abstract: Endogenous period is extended in Myk/ + due to longer periods of (I) activity (α). All data are presented as means ± SEM, *P < 0.05, **P < 0.01; ***P < 0.001 compared with +/+ mice.

Cited by 134 publications

References 63 publications

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

In This Issue/Abstract Thinking: Of Mice, Monkeys, and Men

Basic presynaptic functions in hippocampal neurons are not affected by acute or chronic lithium treatment

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Product

Resources

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Mania-like behavior induced by genetic dysfunction of the neuron-specific Na ⁺ ,K ⁺ -ATPase α3 sodium pump

Abstract: Endogenous period is extended in Myk/ + due to longer periods of (I) activity (α). All data are presented as means ± SEM, P < 0.05, P < 0.01; P < 0.001 compared with +/+ mice.