Person: Vasudevan, Anju
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Vasudevan
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Anju
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Vasudevan, Anju
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Publication Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior(Nature Publishing Group, 2017) Li, Suyan; Kumar T, Peeyush; Joshee, Sampada; Kirschstein, Timo; Subburaju, Sivan; Khalili, Jahan S; Kloepper, Jonas; Du, Chuang; ElKhal, Abdallah; Szabó, Gábor; Jain, Rakesh; Köhling, Rüdiger; Vasudevan, AnjuThe cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3ΔTie2-Cre and VgatΔTie2-Cre), we show that partial or complete loss of GABA release from endothelial cells during embryogenesis results in vascular defects and impairs long-distance migration and positioning of cortical interneurons. The downstream effects of perturbed endothelial cell-derived GABA signaling are critical, leading to lasting changes to cortical circuits and persistent behavioral deficits. Furthermore, we illustrate new mechanisms of activation of GABA signaling in forebrain endothelial cells that promotes their migration, angiogenesis and acquisition of blood-brain barrier properties. Our findings uncover and elucidate a novel endothelial GABA signaling pathway in the CNS that is distinct from the classical neuronal GABA signaling pathway and shed new light on the etiology and pathophysiology of neuropsychiatric diseases, such as autism spectrum disorders, epilepsy, anxiety, depression and schizophrenia.Publication Endothelial GABA signaling: a phoenix awakened(Impact Journals, 2018) Choi, Yong Kee; Vasudevan, AnjuPublication Autonomous Vascular Networks Synchronize GABA Neuron Migration in the Embryonic Forebrain(2013) Won, Chungkil; Lin, Zhicheng; Kumar T, Peeyush; Li, Suyan; Ding, Lai; ElKhal, Abdallah; Szabó, Gábor; Vasudevan, AnjuGABA neurons, born in remote germinative zones in the ventral forebrain (telencephalon), migrate tangentially in two spatially distinct streams to adopt their specific positions in the developing cortex. The cell types and molecular cues that regulate this divided migratory route remains to be elucidated. Here we show that embryonic vascular networks are strategically positioned to fulfill the task of providing support as well as critical guidance cues that regulate the divided migratory routes of GABA neurons in the telencephalon. Interestingly, endothelial cells of the telencephalon are not homogeneous in their gene expression profiles. Endothelial cells of the periventricular vascular network have molecular identities distinct from those of the pial network. Our data suggest that periventricular endothelial cells have intrinsic programs that can significantly mold neuronal development and uncovers new insights into concepts and mechanisms of CNS angiogenesis from both developmental and disease perspectives.Publication NAD+ protects against EAE by regulating CD4+ T-cell differentiation(Nature Pub. Group, 2014) Tullius, Stefan; Biefer, Hector Rodriguez Cetina; Li, Suyan; Trachtenberg, Alexander J.; Edtinger, Karoline; Quante, Markus; Krenzien, Felix; Uehara, Hirofumi; Yang, Xiaoyong; Kissick, Haydn T.; Kuo, Winston P.; Ghiran, Ionita; de la Fuente, Miguel A.; Arredouani, Mohamed Simo; Camacho, Virginia; Tigges, John C.; Toxavidis, Vasilis; El Fatimy, Rachid; Smith, Brian D.; Vasudevan, Anju; ElKhal, AbdallahCD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases.Publication Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale(SAGE Publications, 2017) Rodriguez Cetina Biefer, Hector; Vasudevan, Anju; ElKhal, AbdallahIncreasing evidence underscores the interesting ability of tryptophan to regulate immune responses. However, the exact mechanisms of tryptophan’s immune regulation remain to be determined. Tryptophan catabolism via the kynurenine pathway is known to play an important role in tryptophan’s involvement in immune responses. Interestingly, quinolinic acid, which is a neurotoxic catabolite of the kynurenine pathway, is the major pathway for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+, a natural coenzyme found in all living cells, regulates immune responses and creates homeostasis via a novel signaling pathway. More importantly, the immunoregulatory properties of NAD+ are strongly related to the overexpression of tryptophan hydroxylase 1 (Tph1). This review provides recent knowledge of tryptophan and NAD+ and their specific and intriguing roles in the immune system. Furthermore, it focuses on the mechanisms by which tryptophan regulates NAD+ synthesis as well as innate and adaptive immune responses.Publication NAD+ Mediated Rescue of Prenatal Forebrain Angiogenesis Restores Postnatal Behavior(American Association for the Advancement of Science (AAAS), 2020-10-09) Subburaju, Sivan; Kaye, Sarah; Choi, Yong Kee; Baruah, Jugajyoti; Datta, Debkanya; Ren, Jun; Kumar, Ashwin Srinivasan; Szabo, Gabor; Fukumura, Dai; Jain, Rakesh; ElKhal, Abdallah; Vasudevan, AnjuIntrinsic defects within blood vessels from the earliest developmental time points can directly contribute to psychiatric disease origin. Our work has shown that pre-formed vascular networks autonomously regulate key events during brain development, such as neurogenesis and neuronal migration. Vascular deficits and abnormalities in blood vessels emerging at prenatal stages will persist in the adult brain with direct consequences for blood flow and behavior. Therefore, rescue of abnormal prenatal angiogenesis is pivotal for the rescue of brain development and is a vital aspect for preventing the origin of psychiatric disease. Here we show for the first time, that nicotinamide adenine dinucleotide (NAD+), administered during a critical window of prenatal development in a pre-clinical model of psychiatric disease, results in synergistic repair of impaired angiogenesis and normalization of brain development, thus preventing the acquisition of abnormal behavioral symptoms. The prenatal NAD+ treatment stimulated extensive cellular and molecular changes in endothelial cells, and restored blood vessel formation, GABAergic neuronal development, and forebrain morphology by recruiting an alternate pathway for cellular repair, via new transcriptional mechanisms and purinergic receptor signaling. It rescued the lost neuro-vascular interactions, by restoring endothelial cell-derived GABA, a valuable guidance cue for the long-distance migration of GABAergic interneurons to their final destination in the embryonic forebrain. This rescue of forebrain angiogenesis in the prenatal period was of a permanent and irreversible nature, and significantly improved blood flow in the adult brain. A multi-faceted behavioral phenotype that included stress, anxiety, depression, sociability and cognition were completely cured in this psychiatric disease model. Our findings illustrate a novel and powerful role for NAD+ in sculpting vascular networks during prenatal brain development that has profound implications for rescuing brain blood flow with long lasting consequences for mental health outcome.