A Glutamatergic Network Mediates Lithium Response in Bipolar Disorder as Defined by Epigenome Pathway Analysis

Higgins, Gerald A.; Allyn-Feuer, Ari; Barbour, Edward; Athey, Brian D.

doi:10.2217/pgs.15.106

Cited by 39 publications

(31 citation statements)

References 148 publications

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“…Moreover, in this mouse model the correlation between GSK3, behavior, dendritic spine and glutamatergic synapse phenotypes supports the notion that spines and glutamatergic synapses are critical biological substrates underlying lithium-responsive psychiatric conditions. (53-55). …”

Section: Discussionmentioning

confidence: 99%

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

et al. 2016

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Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals’ brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a Glycogen Synthase Kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9,000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single nucleotide variants (SNVs) in these individuals compared to psychiatrically-unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally-predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.

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Section: Discussionmentioning

confidence: 99%

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

et al. 2016

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“…Finally, cortical pyramidal neurons from a mouse line mutant for the neuronally expressed Wnt/β-catenin pathway activator and DISC1 partner Dixdc1 have reduced dendritic spine and excitatory synapse density correlating with phenotypes in the affective domain (behavioral despair) and social domain (reciprocal social interaction); administration of either lithium or a selective GKS3 inhibitor corrects both the neurodevelopmental and behavioral phenotypes in these animals [343]. This supports that a major neurodevelopmental/neuroplastic target of lithium - and of other psychiatric drugs that either directly or indirectly modulate GSK3 - is the formation, stability, and/or turnover of dendritic spines and glutamatergic synapses [325,344,345]. The same study also provided evidence supporting a “goldilocks principle” for Wnt signaling in these processes at the dendritic spine and synapse, showing that either too much or too little signal pathway activation is similarly deleterious [343].…”

Section: Concluding Remarks: Therapeutic Considerationsmentioning

confidence: 90%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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“…Lithium is commonly used for the treatment of mood disorders and may therefore regulate proteins genetically linked to pathophysiology such as ANK3. Analysis of functional SNPs from GWAS data suggest that AnkG may be involved in the lithium response (33). Lithium has been shown to rescue some BD-related behavioral deficits in different Ank3 KO mouse model (35,41,42), suggesting it can alleviate symptoms of mouse models with AnkG loss of function.…”

Section: Discussionmentioning

confidence: 99%

Palmitoylation controls the stability of 190 kDa Ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium

Piguel

Yoon

DeSimone

et al. 2019

Preprint

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The ANK3 gene, which encodes ankyrin-G (AnkG), is associated with a variety of neuropsychiatric and cognitive disorders including bipolar disorder, autism spectrum disorder, and schizophrenia. These diseases are characterized by abnormal dendritic and synaptic architecture. AnkG is a multifunctional scaffold protein with several isoforms: The 480 kDa and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, but the function of the 190 kDa isoform (AnkG-190) is less well understood. Moreover, AnkG isoforms are regulated by palmitoylation, but palmitoylation of AnkG-190 has not been investigated in neurons. Here we show that AnkG is required for normal dendrite and spine architecture in vivo and that stabilizes pyramidal neuron dendrites. We found that palmitoylation at Cys70 stabilizes in spine heads and at dendritic plasma membrane nanodomains. Finally, we found that lithium, a commonly used mood stabilizer, reduces AnkG-190 palmitoylation and increases its mobility in spines by inhibiting ZDHHC8 action. Taken together, our data reveal a novel mechanism regulating dendritic architecture and mood stabilizer action on palmitoylation of an important psychiatric disorder risk factor. SignificanceThe ANK3 gene has been associated with bipolar disorder and schizophrenia although the mechanisms of disease are not known. The AnkG 190 kDa isoform, AnkG-190, was previously described for its role in dendritic spines. Here, we show it is required to stabilize dendritic arborization and show that palmitoylation, a post-translation modification which allows proteins to stabilize at the membrane, is critical for its localization. Moreover, we show that lithium, a mood stabilizer commonly used in bipolar disorder, modifies AnkG-190 palmitoylation and its dendritic spine localization by inhibiting ZDHHC8 activity, another protein encoded by a psychiatric disorder risk gene. We describe a new novel function for Ank-190 and the early mechanistic actions of lithium in neurons.

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A Glutamatergic Network Mediates Lithium Response in Bipolar Disorder as Defined by Epigenome Pathway Analysis

Cited by 39 publications

References 148 publications

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Palmitoylation controls the stability of 190 kDa Ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium

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