Effects of GADL1 overexpression on cell migration and the associated morphological changes (original) (raw)
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Studying cellular functions in bipolar disorder: Are there specific predictors of lithium response?
Background: Lithium is the first-line mood stabilizer for the treatment of bipolar disorder (BD). In order to interrogate cellular phenotypes related to disease and lithium treatment response, this study used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs) from BD patients who are well characterized for clinical lithium response. Methods: BD patients diagnosed according to the DSM-IV criteria; were recruited from the outpatient services of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Clinical lithium response was assessed using the Alda scale and NIMH Retrospective Life chart method. The controls were ethnically matched healthy subjects with no family history of neuropsychiatric illness. NPCs from two BD patients from the same family who clearly differed in their clinical response to lithium were chosen, and compared with healthy population controls. Whole transcriptome sequencing (RNA-Seq) and analysis were performed, wit...
Scientific Reports
Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the “Alda scale” and “NIMH Retrospective Life chart method”), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in...
Neurotrophic signaling cascades are major long-term targets for lithium: clinical implications
Clinical Neuroscience Research, 2004
Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. In this perspective paper, we discuss the preclinical and clinical evidence that lithium has neuroprotective and neurotrophic effects, and furthermore, show that these effects may have great relevance for the optimal treatment of severe mood disorders. Lithium has been noted to have neuroprotective effects in cell culture, and in animal models of neurodegeneration such as stroke, Huntington's disease and Alzheimer's disease. This may be due to the findings that lithium regulates the expression and/or activity of numerous molecules and enzymes involved in neuroplasticity, neuroprotection and mitochondrial function including bcl-2, GSK-3 and the ERK/MAP kinase pathway. Emerging clinical evidence additionally suggests that lithium may have similar effects in patients; these findings include an increase in N-acetyl aspartate (NAA) and gray matter in patients following long-term lithium treatment. Together, the data has implications not only for the optimal treatment of severe mood disorders, but potentially also for the treatment of other, more classical, neurodegenerative disorders.
Lithium Mechanism of lithium action Neuroprotective effects of lithium Bipolar illness is a major psychiatric disorder that affects 1–3% of the worldwide population. Epidemiological studies have demonstrated that this illness is substantially heritable. However, the genetic characteristics remain unknown and a clear personality has not been identified for these patients. The clinical history of lithium began in mid-19th century when it was used to treat gout. In 1940, it was used as a substitute for sodium chloride in hypertensive patients. However, it was then banned, as it had major side effects. In 1949, Cade reported that lithium could be used as an effective treatment for bipolar disorder and subsequent studies confirmed this effect. Over the years, different authors have proposed many biochemical and biological effects of lithium in the brain. In this review, the main mechanisms of lithium action are summarised, including ion dysregulation; effects on neurotransmitter signalling; the interaction of lithium with the adenylyl cyclase system; inositol phosphate and protein kinase C signalling; and possible effects on arachidonic acid metabolism. However, none of the above mechanisms are definitive, and sometimes results have been contradictory. Recent advances in cellular and molecular biology have reported that lithium may represent an effective therapeutic strategy for treating neurodegenerative disorders like Alzheimer's disease, due to its effects on neuroprotective proteins like Bcl-2 and its actions on regulators of apoptosis and cellular resilience, such as GSK-3. However, results are contradictory and more specific studies into the use of lithium in therapeutic approaches for neurodegenerative diseases are required.
Pharmacological Research, 2008
A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score<or=6). Our negative findings do not exclude involvement of PDLIM5 in lithium prophylaxis, and further investigation is warranted.
Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics
Molecular psychiatry, 2015
After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by the absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na(+)-K(+) ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need...
Biological Targets Underlying the Antisuicidal Effects of Lithium
Current Behavioral Neuroscience Reports, 2020
Purpose of Review This article highlights the potential relationship of lithium's cellular and molecular targets to its antisuicidal effects in bipolar disorder (BD). Recent Findings Lithium is the mood stabilizer that shows the most robust therapeutic evidence in relapse prevention and mood episodes in BD. Compelling evidence also elucidates lithium's unique effects in reversing and preventing suicidal behavior (SB), mostly in individuals with BD. Summary The following review is an up-to-date summary of studies related to the anti-suicidal effects of lithium in patients with BD. We focused on studies investigating the similarities in pathogenesis of BD and SB and the related treatment targets for lithium's anti-suicidal actions. Lithium seems to have beneficial effects in reversing pathophysiological changes in SB and BD associated with its ability to reduce suicidal risk. Several neurobiological targets have been associated with the antisuicidal effects of lithium such as brain atrophy and demyelination, alterations in glutamatergic neurotransmission, and increased central and peripheral inflammation as well as HPA axis hyperactivation, cell signaling pathways, and neurotrophic system dysfunctions. Further studies are required to elucidate the presence of a specific neurobiological signature of SB as an independent clinical dimension and not solely in the context of mood episodes.
Aim: A regulatory network in the human brain mediating lithium response in bipolar patients was revealed by analysis of functional SNPs from genome-wide association studies (GWAS) and published gene association studies, followed by epigenome mapping. Methods: An initial set of 23,312 SNPs in linkage disequilibrium with lead SNPs, and sub-threshold GWAS SNPs rescued by pathway analysis, were studied in the same populations. These were assessed using our workflow and annotation by the epigenome roadmap consortium. Results: Twenty-seven percent of 802 SNPs that were associated with lithium response (13 published studies gene association studies and two GWAS) were shared in common with 1281 SNPs from 18 GWAS examining psychiatric disorders and adverse events associated with lithium treatment. Nineteen SNPs were annotated as active regulatory elements such as enhancers and promoters in a tissue-specific manner. They were located within noncoding regions of ten genes: ANK3, ARNTL, CACNA1C, CACNG2, CDKN1A, CREB1, GRIA2, GSK3B, NR1D1 and SLC1A2. Following gene set enrichment and pathway analysis, these genes were found to be significantly associated (p = 10 -27 ; Fisher exact test) with an AMPA2 glutamate receptor network in human brain. Our workflow results showed concordance with annotation of regulatory elements from the epigenome roadmap. Analysis of cognate mRNA and enhancer RNA exhibited patterns consistent with an integrated pathway in humanbrain. Conclusion: This pharmacoepigenomic regulatory pathway is located in the same brain regions that exhibit tissue volume loss in bipolar disorder. Although in silico analysis requires biological validation, the approach provides value for identification of candidate variants that may be used in pharmacogenomic testing to identify bipolar patients likely to respond to lithium.
Overview of the mechanism of action of lithium in the brain: fifty-year update
The Journal of clinical psychiatry, 2000
Since its discovery, lithium has been shown to act upon various neurotransmitter systems at multiple levels of signaling in the brain. Lithium, affecting each neurotransmitter system within complex interactive neuronal networks, is suggested to restore the balance among aberrant signaling pathways in critical regions of the brain. Recent molecular studies have revealed the action of lithium on signal transduction mechanisms, such as phosphoinositide hydrolysis, adenylyl cyclase, G protein, glycogen synthase kinase-3beta, protein kinase C, and its substrate myristoylated alanine-rich C kinase substrate. Such effects are thought to trigger long-term changes in neuronal signaling patterns that account for the prophylactic properties of lithium in the treatment of bipolar disorder. Through its effects on glycogen synthase kinase-3beta and protein kinase C, lithium may alter the level of phosphorylation of cytoskeletal proteins, which leads to neuroplastic changes associated with mood st...