Browsing by Author "Marchetto, Maria C."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.
    (NPG, 2015-11-05) Mertens, Jerome; Wang, Qiu-Wen; Kim, Yongsung; Yu, Diana X.; Pham, Son; Yang, Bo; Zheng, Yi; Diffenderfer, Kenneth E.; Zhang, Jian; Soltani, Sheila; Eames, Tameji; Schafer, Simon T.; Boyer, Leah; Marchetto, Maria C.; Nurnberger, John I.; Calabrese, Joseph R.; Oedegaard, Ketil J.; McCarthy, Michael J.; Zandi, Peter P.; Alda, Martin; Nievergelt, Caroline M.; Mi, Shuangli; Brennand, Kristen J.; Kelsoe, John R.; Gage, Fred H.; Yao, Jun; Department of Psychiatry, IU School of Medicine
    Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
  • Thumbnail Image
    Item
    Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis
    (Springer Nature, 2024) Niemsiri, Vipavee; Rosenthal, Sara Brin; Nievergelt, Caroline M.; Maihofer, Adam X.; Marchetto, Maria C.; Santos, Renata; Shekhtman, Tatyana; Alliey-Rodriguez, Ney; Anand, Amit; Balaraman, Yokesh; Berrettini, Wade H.; Bertram, Holli; Burdick, Katherine E.; Calabrese, Joseph R.; Calkin, Cynthia V.; Conroy, Carla; Coryell, William H.; DeModena, Anna; Eyler, Lisa T.; Feeder, Scott; Fisher, Carrie; Frazier, Nicole; Frye, Mark A.; Gao, Keming; Garnham, Julie; Gershon, Elliot S.; Goes, Fernando S.; Goto, Toyomi; Harrington, Gloria J.; Jakobsen, Petter; Kamali, Masoud; Kelly, Marisa; Leckband, Susan G.; Lohoff, Falk W.; McCarthy, Michael J.; McInnis, Melvin G.; Craig, David; Millett, Caitlin E.; Mondimore, Francis; Morken, Gunnar; Nurnberger, John I.; O'Donovan, Claire; Øedegaard, Ketil J.; Ryan, Kelly; Schinagle, Martha; Shilling, Paul D.; Slaney, Claire; Stapp, Emma K.; Stautland, Andrea; Tarwater, Bruce; Zandi, Peter P.; Alda, Martin; Fisch, Kathleen M.; Gage, Fred H.; Kelsoe, John R.; Psychiatry, School of Medicine
    Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.