Publications by authors named "Moses V Chao"

153 Publications

Hippocampal metabolite concentrations in schizophrenia vary in association with rare gene variants in the TRIO gene.

Schizophr Res 2020 10 9;224:167-169. Epub 2020 Nov 9.

Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University, NY, NY, USA; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.

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http://dx.doi.org/10.1016/j.schres.2020.11.001DOI Listing
October 2020

Stoichiometry counts.

Authors:
Moses V Chao

Proc Natl Acad Sci U S A 2019 10 16;116(43):21343-21345. Epub 2019 Sep 16.

Skirball Institute of Biomolecular Medicine, New York University Langone School of Medicine, New York, NY 10012

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http://dx.doi.org/10.1073/pnas.1914583116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815164PMC
October 2019

Rapamycin blocks the neuroprotective effects of sex steroids in the adult birdsong system.

Dev Neurobiol 2019 08 23;79(8):794-804. Epub 2019 Sep 23.

Departments of Psychology and Biology, Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington.

In adult songbirds, the telencephalic song nucleus HVC and its efferent target RA undergo pronounced seasonal changes in morphology. In breeding birds, there are increases in HVC volume and total neuron number, and RA neuronal soma area compared to nonbreeding birds. At the end of breeding, HVC neurons die through caspase-dependent apoptosis and thus, RA neuron size decreases. Changes in HVC and RA are driven by seasonal changes in circulating testosterone (T) levels. Infusing T, or its metabolites 5α-dihydrotestosterone (DHT) and 17 β-estradiol (E2), intracerebrally into HVC (but not RA) protects HVC neurons from death, and RA neuron size, in nonbreeding birds. The phosphoinositide 3-kinase (PI3K)-Akt (a serine/threonine kinase)-mechanistic target of rapamycin (mTOR) signaling pathway is a point of convergence for neuroprotective effects of sex steroids and other trophic factors. We asked if mTOR activation is necessary for the protective effect of hormones in HVC and RA of adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii). We transferred sparrows from breeding to nonbreeding hormonal and photoperiod conditions to induce regression of HVC neurons by cell death and decrease of RA neuron size. We infused either DHT + E2, DHT + E2 plus the mTOR inhibitor rapamycin, or vehicle alone in HVC. Infusion of DHT + E2 protected both HVC and RA neurons. Coinfusion of rapamycin with DHT + E2, however, blocked the protective effect of hormones on HVC volume and neuron number, and RA neuron size. These results suggest that activation of mTOR is an essential downstream step in the neuroprotective cascade initiated by sex steroid hormones in the forebrain.
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http://dx.doi.org/10.1002/dneu.22719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823113PMC
August 2019

Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor.

Mol Cell Neurosci 2019 09 15;99:103395. Epub 2019 Aug 15.

Departments of Cell Biology, Physiology & Neuroscience, and Psychiatry, Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, New York 10016, USA. Electronic address:

BACE1 is a transmembrane aspartic protease that cleaves various substrates and it is required for normal brain function. BACE1 expression is high during early development, but it is reduced in adulthood. Under conditions of stress and injury, BACE1 levels are increased; however, the underlying mechanisms that drive BACE1 elevation are not well understood. One mechanism associated with brain injury is the activation of injurious p75 neurotrophin receptor (p75), which can trigger pathological signals. Here we report that within 72 h after controlled cortical impact (CCI) or laser injury, BACE1 and p75 are increased and tightly co-expressed in cortical neurons of mouse brain. Additionally, BACE1 is not up-regulated in p75 null mice in response to focal cortical injury, while p75 over-expression results in BACE1 augmentation in HEK-293 and SY5Y cell lines. A luciferase assay conducted in SY5Y cell line revealed that BACE1 expression is regulated at the transcriptional level in response to p75 transfection. Interestingly, this effect does not appear to be dependent upon p75 ligands including mature and pro-neurotrophins. In addition, BACE1 activity on amyloid precursor protein (APP) is enhanced in SY5Y-APP cells transfected with a p75 construct. Lastly, we found that the activation of c-jun n-terminal kinase (JNK) by p75 contributes to BACE1 up-regulation. This study explores how two injury-induced molecules are intimately connected and suggests a potential link between p75 signaling and the expression of BACE1 after brain injury.
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http://dx.doi.org/10.1016/j.mcn.2019.103395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993608PMC
September 2019

Brain-derived neurotrophic factor (BDNF) and TrkB hippocampal gene expression are putative predictors of neuritic plaque and neurofibrillary tangle pathology.

Neurobiol Dis 2019 12 23;132:104540. Epub 2019 Jul 23.

Department of Neurobiology and Neurology, Barrow Neurological Institute, Phoenix, AZ, United States of America.

Introduction: Downregulation of brain-derived neurotrophic factor (BDNF) and its cognate neurotrophin receptor, TrkB, were observed during the progression of dementia, but whether the Alzheimer's disease (AD) pathological lesions diffuse plaques, (DPs), neuritic plaques (NPs), and neurofibrillary tangles (NFTs) are related to this alteration remains to be clarified.

Methods: Negative binomial (NB) regressions were performed using gene expression data accrued from a single population of CA1 pyramidal neurons and regional hippocampal dissections obtained from participants in the Rush Religious Orders Study (RROS).

Results: Downregulation of Bdnf is independently associated with increased entorhinal cortex NPs. Downregulation of TrkB is independently associated with increased entorhinal cortex NFTs and CA1 NPs during the progression of AD.

Discussion: Results indicate that BDNF and TrkB dysregulation contribute to AD neuropathology, most notably hippocampal NPs and NFTs. These data suggest attenuating BDNF/TrkB signaling deficits either at the level of BDNF, TrkB, or downstream of TrkB signaling may abrogate NPs and/or NFTs.
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http://dx.doi.org/10.1016/j.nbd.2019.104540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834890PMC
December 2019

TOP2β-Dependent Nuclear DNA Damage Shapes Extracellular Growth Factor Responses via Dynamic AKT Phosphorylation to Control Virus Latency.

Mol Cell 2019 05 28;74(3):466-480.e4. Epub 2019 Mar 28.

Department of Biochemistry & Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival, and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. We demonstrate that endogenous DNA double-strand breaks (DSBs) mediated by Topoisomerase 2β-DNA cleavage complex (TOP2βcc) intermediates are required to achieve AKT-mTORC1 signaling and maintain HSV-1 latency in neurons. Suppression of host DNA-repair pathways that remove TOP2βcc trigger HSV-1 reactivation. Moreover, perturbation of AKT phosphorylation dynamics by downregulating the PHLPP1 phosphatase led to AKT mis-localization and disruption of DSB-induced HSV-1 reactivation. Thus, the cellular genome integrity and environmental inputs are consolidated and co-opted by a latent virus to balance lifelong infection with transmission.
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http://dx.doi.org/10.1016/j.molcel.2019.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499694PMC
May 2019

Methylphenidate alters Akt-mTOR signaling in rat pheochromocytoma cells.

Int J Dev Neurosci 2019 Apr 19;73:10-18. Epub 2018 Dec 19.

Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Programa de Pós‑Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

The exponential increase in methylphenidate (MPH) prescriptions in recent years has worried researchers about its misuse among individuals who do not meet the full diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) such as young children and students in search of cognitive improvement or for recreational reasons. The action of MPH is based mainly on inhibition of dopamine transporter, but the complete cellular effects are still unknown. Based upon prior studies, we attempted to determine whether the treatment with MPH (1μM) influences protein kinase B-mammalian target of rapamycin complex 1 signaling pathways (Akt-mTOR), including translation repressor protein (4E-BP1) and mitogen activated protein kinase (S6K), in rat pheochromocytoma cells (PC12), a well characterized cellular model, in a long or short term. MPH effects on the Akt substrates [cAMP response element-binding protein (CREB), forkhead box protein O1 (FoxO1), and glycogen synthase kinase 3 beta (GSK-3β)] were also evaluated. Whereas short term MPH treatment decreased the pAkt/Akt, pmTOR/mTOR and pS6K/S6K ratios, as well as pFoxO1 immunocontent in PC12 cells, long term treatment increased pAkt/Akt, pmTOR/mTOR and pGSK-3β/GSK-3β ratio. Phosphorylation levels of 4E-BP1 were decreased at 15 and 30 min and increased at 1 and 6 h by MPH. pCREB/CREB ratio was decreased. This study shows that the Akt-mTOR pathway, as well as other important Akt substrates which have been described as important regulators of protein synthesis, as well as being implicated in cellular survival, synaptic plasticity and memory consolidation, was affected by MPH in PC12 cells, representing an important step in exploring the MPH effects.
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http://dx.doi.org/10.1016/j.ijdevneu.2018.12.004DOI Listing
April 2019

Bridging the Gap between Brain-Derived Neurotrophic Factor and Glucocorticoid Effects on Brain Networks.

Neuroendocrinology 2019 20;109(3):277-284. Epub 2018 Dec 20.

New York University Langone Medical Center, New York, New York, USA.

Behavioral choices made by the brain during stress depend on glucocorticoid and brain-derived neurotrophic factor (BDNF) signaling pathways acting in synchrony in the mesolimbic (reward) and corticolimbic (emotion) neural networks. Deregulated expression of BDNF and glucocorticoid receptors in brain valuation areas may compromise the integration of signals. Glucocorticoid receptor phosphorylation upon BDNF signaling in neurons represents one mechanism underlying the integration of BDNF and glucocorticoid signals that when off balance may lay the foundation of maladaptations to stress. Here, we propose that BDNF signaling conditions glucocorticoid responses impacting neural plasticity in the mesocorticolimbic system. This provides a novel molecular framework for understanding how brain networks use BDNF and glucocorticoid signaling contingencies to forge receptive neuronal fields in temporal domains defined by behavioral experience, and in mood disorders.
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http://dx.doi.org/10.1159/000496392DOI Listing
June 2020

Traumatic experiences and cognitive profiles of schizophrenia cases influenced by the BDNF Val66met polymorphism.

Psychiatry Res 2019 01 15;271:111-113. Epub 2018 Nov 15.

Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY, USA; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Germany.

The association of early trauma exposure with current cognition was examined in a research series of 56 schizophrenia cases with respect to the BDNF Val66Met polymorphism (rs6265, Val66Val, Val66Met, Met66Met), as met allele carriers have reduced neurotrophic activity. The Perceptual Organization Index had a significant negative correlation with trauma exposures only in met carriers, including early physical abuse, general trauma after age 18 years, and physical abuse. Within the Val66Val subgroup, there were no significant correlations between WAIS indices and traumatic experiences.
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http://dx.doi.org/10.1016/j.psychres.2018.11.029DOI Listing
January 2019

Oxytocin Transforms Firing Mode of CA2 Hippocampal Neurons.

Neuron 2018 11 4;100(3):593-608.e3. Epub 2018 Oct 4.

NYU Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Oxytocin is an important neuromodulator in the mammalian brain that increases information salience and circuit plasticity, but its signaling mechanisms and circuit effect are not fully understood. Here we report robust oxytocinergic modulation of intrinsic properties and circuit operations in hippocampal area CA2, a region of emerging importance for hippocampal function and social behavior. Upon oxytocin receptor activation, CA2 pyramidal cells depolarize and fire bursts of action potentials, a consequence of phospholipase C signaling to modify two separate voltage-dependent ionic processes. A reduction of potassium current carried by KCNQ-based M channels depolarizes the cell; protein kinase C activity attenuates spike rate of rise and overshoot, dampening after-hyperpolarizations. These actions, in concert with activation of fast-spiking interneurons, promote repetitive firing and CA2 bursting; bursting then governs short-term plasticity of CA2 synaptic transmission onto CA1 and, thus, efficacy of information transfer in the hippocampal network.
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http://dx.doi.org/10.1016/j.neuron.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516476PMC
November 2018

Rare missense coding variants in oxytocin receptor (OXTR) in schizophrenia cases are associated with early trauma exposure, cognition and emotional processing.

J Psychiatr Res 2018 02 22;97:58-64. Epub 2017 Nov 22.

Departments of Psychiatry, Neuroscience and Genetics, Icahn School of Medicine at Mt. Sinai Medical Center, New York, NY, USA.

Background: Oxytocin is a peptide hormone that influences the integration of social cognition with behavior and affect regulation. Oxytocin also prominently directs the transition of neuronal GABA neurotransmission from excitatory to inhibitory after birth. The oxytocin receptor (OXTR) is linked to schizophrenia, a heterogeneous syndrome. Relationships of OXTR polymorphisms with specific clinical features could aid in evaluating any role of oxytocin in the pathogenesis of schizophrenia.

Method: Schizophrenia cases with rare missense coding OXTR single nucleotide variants (SNVs) were identified from a well-characterized sample of cases and controls who were assessed for symptoms, cognition and early life trauma.

Results: Five of 48 cases showed rare OXTR variants. Compared to the other cases they had less severe negative symptoms (deficits in emotional expression and motivation) and less severe general psychopathology scores (depression and anxiety). They demonstrated lower nonverbal (performance) than verbal intelligence due to deficient perceptual organization and slow processing speed. They also reported greater early trauma exposure (physical and sexual abuse and emotional trauma).

Conclusion: Cases carrying rare OXTR SNVs had less negative and affective symptoms than other cases, but similar psychotic symptoms, along with specific cognitive deficits. The clinical characterization of these cases occurred in association with environmental exposure to early trauma, especially sexual abuse, which may have influenced the expression of schizophrenia in subjects harboring specific SNVs in the OXTR.
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http://dx.doi.org/10.1016/j.jpsychires.2017.11.011DOI Listing
February 2018

Sex-Specific Differences in Oxytocin Receptor Expression and Function for Parental Behavior.

Gend Genome 2017 Dec;1(4):142-166

Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York.

Parental care is among the most profound behavior expressed by humans and other animals. Despite intense interest in understanding the biological basis of parental behaviors, it remains unknown how much of parenting is encoded by the genome and which abilities instead are learned or can be refined by experience. One critical factor at the intersection between innate behaviors and experience-dependent learning is oxytocin, a neurohormone important for maternal physiology and neuroplasticity. Oxytocin acts throughout the body and brain to promote prosocial and maternal behaviors and modulates synaptic transmission to affect neural circuit dynamics. Recently we developed specific antibodies to mouse oxytocin receptors, found that oxytocin receptors are left lateralized in female auditory cortex, and examined how oxytocin enables maternal behavior by sensitizing the cortex to infant distress sounds. In this study we compare oxytocin receptor expression and function in male and female mice. Receptor expression is higher in adult female left auditory cortex than in right auditory cortex or males. Developmental profiles and mRNA expression were comparable between males and females. Behaviorally, male and female mice began expressing parental behavior similarly after cohousing with experienced females; however, oxytocin enhanced parental behavior onset in females but not males. This suggests that left lateralization of oxytocin receptor expression in females provides a mechanism for accelerating maternal behavior onset, although male mice can also effectively co-parent after experience with infants. The sex-specific pattern of oxytocin receptor expression might genetically predispose female cortex to respond to infant cues, which both males and females can also rapidly learn.
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http://dx.doi.org/10.1089/gg.2017.0017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500123PMC
December 2017

Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease.

Hippocampus 2019 05 27;29(5):422-439. Epub 2017 Sep 27.

Department of Neurobiology and Neurology, Barrow Neurological Institute, Phoenix, Arizona.

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD.
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http://dx.doi.org/10.1002/hipo.22802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844851PMC
May 2019

p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis.

J Neurochem 2018 02 27;144(3):302-317. Epub 2017 Sep 27.

School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.
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http://dx.doi.org/10.1111/jnc.14206DOI Listing
February 2018

Oxytocin Modulation of Neural Circuits.

Curr Top Behav Neurosci 2018;35:31-53

Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY, USA.

Oxytocin is a hypothalamic neuropeptide first recognized as a regulator of parturition and lactation which has recently gained attention for its ability to modulate social behaviors. In this chapter, we review several aspects of the oxytocinergic system, focusing on evidence for release of oxytocin and its receptor distribution in the cortex as the foundation for important networks that control social behavior. We examine the developmental timeline of the cortical oxytocin system as demonstrated by RNA, autoradiographic binding, and protein immunohistochemical studies, and describe how that might shape brain development and behavior. Many recent studies have implicated oxytocin in cognitive processes such as processing of sensory stimuli, social recognition, social memory, and fear. We review these studies and discuss the function of oxytocin in the young and adult cortex as a neuromodulator of central synaptic transmission and mediator of plasticity.
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http://dx.doi.org/10.1007/7854_2017_7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834368PMC
October 2018

The transmembrane domain of the p75 neurotrophin receptor stimulates phosphorylation of the TrkB tyrosine kinase receptor.

J Biol Chem 2017 10 17;292(40):16594-16604. Epub 2017 Aug 17.

From the Departments of Cell Biology, Physiology & Neuroscience, and Psychiatry, Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, New York 10016.

The function of protein products generated from intramembraneous cleavage by the γ-secretase complex is not well defined. The γ-secretase complex is responsible for the cleavage of several transmembrane proteins, most notably the amyloid precursor protein that results in Aβ, a transmembrane (TM) peptide. Another protein that undergoes very similar γ-secretase cleavage is the p75 neurotrophin receptor. However, the fate of the cleaved p75 TM domain is unknown. p75 neurotrophin receptor is highly expressed during early neuronal development and regulates survival and process formation of neurons. Here, we report that the p75 TM can stimulate the phosphorylation of TrkB (tyrosine kinase receptor B). phosphorylation experiments indicated that a peptide representing p75 TM increases TrkB phosphorylation in a dose- and time-dependent manner. Moreover, mutagenesis analyses revealed that a valine residue at position 264 in the rat p75 neurotrophin receptor is necessary for the ability of p75 TM to induce TrkB phosphorylation. Because this residue is just before the γ-secretase cleavage site, we then investigated whether the p75(αγ) peptide, which is a product of both α- and γ-cleavage events, could also induce TrkB phosphorylation. Experiments using TM domains from other receptors, EGFR and FGFR1, failed to stimulate TrkB phosphorylation. Co-immunoprecipitation and biochemical fractionation data suggested that p75 TM stimulates TrkB phosphorylation at the cell membrane. Altogether, our results suggest that TrkB activation by p75(αγ) peptide may be enhanced in situations where the levels of the p75 receptor are increased, such as during brain injury, Alzheimer's disease, and epilepsy.
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http://dx.doi.org/10.1074/jbc.M117.788729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633122PMC
October 2017

Transglutaminase-5 related schizophrenia.

Schizophr Res 2018 03 7;193:477-479. Epub 2017 Aug 7.

Department of Psychiatry, New York University School of Medicine, New York, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2017.08.004DOI Listing
March 2018

The Emerging Role for Zinc in Depression and Psychosis.

Front Pharmacol 2017 30;8:414. Epub 2017 Jun 30.

Department of Psychiatry, New York University School of MedicineNew York, NY, United States.

Zinc participation is essential for all physiological systems, including neural functioning, where it participates in a myriad of cellular processes. Converging clinical, molecular, and genetic discoveries illuminate key roles for zinc homeostasis in association with clinical depression and psychosis which are not yet well appreciated at the clinical interface. Intracellular deficiency may arise from low circulating zinc levels due to dietary insufficiency, or impaired absorption from aging or medical conditions, including alcoholism. A host of medications commonly administered to psychiatric patients, including anticonvulsants, oral medications for diabetes, hormones, antacids, anti-inflammatories and others also impact zinc absorption. Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range. Well powered clinical studies have shown beneficial effects of supplemental zinc in depression and it important to pursue research using zinc as a potential therapeutic option for psychosis as well. Meta-analyses support the adjunctive use of zinc in major depression and a single study now supports zinc for psychotic symptoms. This manuscript reviews the biochemistry and bench top evidence on putative molecular mechanisms of zinc as a psychiatric treatment.
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http://dx.doi.org/10.3389/fphar.2017.00414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492454PMC
June 2017

Early trauma and clinical features of schizophrenia cases influenced by the BDNF Val66Met allele.

Schizophr Res 2018 03 12;193:453-455. Epub 2017 Jul 12.

Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University, NY, NY, USA.

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http://dx.doi.org/10.1016/j.schres.2017.06.061DOI Listing
March 2018

Immune Escape via a Transient Gene Expression Program Enables Productive Replication of a Latent Pathogen.

Cell Rep 2017 01;18(5):1312-1323

Department of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center at NYU Medical Center, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA. Electronic address:

How type I and II interferons prevent periodic reemergence of latent pathogens in tissues of diverse cell types remains unknown. Using homogeneous neuron cultures latently infected with herpes simplex virus 1, we show that extrinsic type I or II interferon acts directly on neurons to induce unique gene expression signatures and inhibit the reactivation-specific burst of viral genome-wide transcription called phase I. Surprisingly, interferons suppressed reactivation only during a limited period early in phase I preceding productive virus growth. Sensitivity to type II interferon was selectively lost if viral ICP0, which normally accumulates later in phase I, was expressed before reactivation. Thus, interferons suppress reactivation by preventing initial expression of latent genomes but are ineffective once phase I viral proteins accumulate, limiting interferon action. This demonstrates that inducible reactivation from latency is only transiently sensitive to interferon. Moreover, it illustrates how latent pathogens escape host immune control to periodically replicate by rapidly deploying an interferon-resistant state.
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http://dx.doi.org/10.1016/j.celrep.2017.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340258PMC
January 2017

Neurotrophin signalling: novel insights into mechanisms and pathophysiology.

Clin Sci (Lond) 2017 01;131(1):13-23

Neuroscience and Physiology and Psychiatry, New York University School of Medicine, New York, NY 10016, U.S.A.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are prominent regulators of neuronal survival, growth and differentiation during development. While trophic factors are viewed as well-understood but not innovative molecules, there are many lines of evidence indicating that BDNF plays an important role in the pathophysiology of many neurodegenerative disorders, depression, anxiety and other psychiatric disorders. In particular, lower levels of BDNF are associated with the aetiology of Alzheimer's and Huntington's diseases. A major challenge is to explain how neurotrophins are able to induce plasticity, improve learning and memory and prevent age-dependent cognitive decline through receptor signalling. This article will review the mechanism of action of neurotrophins and how BDNF/tropomyosin receptor kinase B (TrkB) receptor signaling can dictate trophic responses and change brain plasticity through activity-dependent stimulation. Alternative approaches for modulating BDNF/TrkB signalling to deliver relevant clinical outcomes in neurodegenerative and neuropsychiatric disorders will also be described.
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http://dx.doi.org/10.1042/CS20160044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295469PMC
January 2017

Deletion of Neurotrophin Signaling through the Glucocorticoid Receptor Pathway Causes Tau Neuropathology.

Sci Rep 2016 11 16;6:37231. Epub 2016 Nov 16.

Inserm, U1191, Institute of Functional Genomics, F-34000 Montpellier, France.

Glucocorticoid resistance is a risk factor for Alzheimer's disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance. We report that deletion of GR phosphorylation at BDNF-responding sites and downstream signaling via the MAPK-phosphatase DUSP1 triggers tau phosphorylation and dendritic spine atrophy in mouse cortex. In human cortex, DUSP1 protein expression correlates with tau phosphorylation, synaptic defects and cognitive decline in subjects diagnosed with AD. These findings provide evidence for a causal role of BDNF-dependent GR signaling in tau neuropathology and indicate that DUSP1 is a potential target for therapeutic interventions.
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http://dx.doi.org/10.1038/srep37231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110980PMC
November 2016

Intercellular Networks Underlying Developmental Decisions.

Authors:
Moses V Chao

Neuron 2016 Sep;91(5):947-949

Departments of Cell Biology, Physiology & Neuroscience, and Psychiatry, Skirball Institute of Biomolecular Medicine, New York University Langone Medical School, New York, NY 10016, USA. Electronic address:

In this issue of Neuron, Yuzwa et al. (2016) identify secreted factors that influence the cell fates of embryonic neural progenitor cells. Surprisingly, the major contributors are trophic factors from the GDNF family and a cytokine, interferon-γ. Advanced analysis of proteomic and transcriptome data discovered ligand receptors that influence cell-cell communication.
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http://dx.doi.org/10.1016/j.neuron.2016.08.025DOI Listing
September 2016

Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.

Elife 2016 06 2;5. Epub 2016 Jun 2.

Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.
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http://dx.doi.org/10.7554/eLife.15092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915811PMC
June 2016

Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes.

EBioMedicine 2016 Apr 8;6:206-214. Epub 2016 Mar 8.

Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Background: Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample.

Method: Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls.

Findings: Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n=5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n=4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n=4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n=5). Case vignettes are included in the appendix.

Interpretation: Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders.
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http://dx.doi.org/10.1016/j.ebiom.2016.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856793PMC
April 2016

Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology.

Neural Regen Res 2016 Mar;11(3):363-7

Departments of Cell Biology, Physiology, and Neuroscience and Psychiatry, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, USA.

Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity, learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures, while the majority of studies on synaptic plasticity, learning and memory were performed in acute brain slices or in vivo. A recent study by Bowling-Bhattacharya et al., measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice. In this paper, we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain.
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http://dx.doi.org/10.4103/1673-5374.179031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828984PMC
March 2016

Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing.

Neuron 2016 05 21;90(3):609-21. Epub 2016 Apr 21.

Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany. Electronic address:

Oxytocin promotes social interactions and recognition of conspecifics that rely on olfaction in most species. The circuit mechanisms through which oxytocin modifies olfactory processing are incompletely understood. Here, we observed that optogenetically induced oxytocin release enhanced olfactory exploration and same-sex recognition of adult rats. Consistent with oxytocin's function in the anterior olfactory cortex, particularly in social cue processing, region-selective receptor deletion impaired social recognition but left odor discrimination and recognition intact outside a social context. Oxytocin transiently increased the drive of the anterior olfactory cortex projecting to olfactory bulb interneurons. Cortical top-down recruitment of interneurons dynamically enhanced the inhibitory input to olfactory bulb projection neurons and increased the signal-to-noise of their output. In summary, oxytocin generates states for optimized information extraction in an early cortical top-down network that is required for social interactions with potential implications for sensory processing deficits in autism spectrum disorders.
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http://dx.doi.org/10.1016/j.neuron.2016.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860033PMC
May 2016

Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease.

Neurobiol Dis 2017 01 22;97(Pt B):73-79. Epub 2016 Mar 22.

Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, United States; Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, 10016, United States; Department of Psychiatry, New York University School of Medicine, New York, NY, 10016, United States; Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY, 10016, United States.

Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease.
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http://dx.doi.org/10.1016/j.nbd.2016.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295364PMC
January 2017

ARMS/Kidins220 and synembryn-B levels regulate NGF-mediated secretion.

J Cell Sci 2016 05 10;129(9):1866-77. Epub 2016 Mar 10.

Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), University of Salamanca, Salamanca 37007, Spain Institute of Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain

Proper development of the nervous system requires a temporally and spatially orchestrated set of events including differentiation, synapse formation and neurotransmission. Nerve growth factor (NGF) acting through the TrkA neurotrophin receptor (also known as NTRK1) regulates many of these events. However, the molecular mechanisms responsible for NGF-regulated secretion are not completely understood. Here, we describe a new signaling pathway involving TrkA, ARMS (also known as Kidins220), synembryn-B and Rac1 in NGF-mediated secretion in PC12 cells. Whereas overexpression of ARMS blocked NGF-mediated secretion, without affecting basal secretion, a decrease in ARMS resulted in potentiation. Similar effects were observed with synembryn-B, a protein that interacts directly with ARMS. Downstream of ARMS and synembryn-B are Gαq and Trio proteins, which modulate the activity of Rac1 in response to NGF. Expression of dominant-negative Rac1 rescued the secretion defects of cells overexpressing ARMS or synembryn-B. Thus, this neurotrophin pathway represents a new mechanism responsible for NGF-regulated secretion.
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http://dx.doi.org/10.1242/jcs.184168DOI Listing
May 2016

A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

Neuron 2016 Mar 3;89(6):1291-1304. Epub 2016 Mar 3.

Schaller Research Group on Neuropeptides at German Cancer Research Center (DKFZ) and Cell Network Cluster of Excellence at the University of Heidelberg, Heidelberg 69120, Germany; Max Planck Institute for Medical Research, Heidelberg 69120, Germany; Central Institute of Mental Health (ZI), Mannheim 68159, Germany. Electronic address:

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.
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http://dx.doi.org/10.1016/j.neuron.2016.01.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679079PMC
March 2016