Publications by authors named "Barbara Porton"

20 Publications

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Molecular markers of neuroendocrine function and mitochondrial biogenesis associated with early life stress.

Psychoneuroendocrinology 2020 06 20;116:104632. Epub 2020 Feb 20.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA; Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.

Objective: Glucocorticoid receptor gene (NR3C1) promoter methylation influences cellular expression of the glucocorticoid receptor and is a proposed mechanism by which early life stress impacts neuroendocrine function. Mitochondria are sensitive and responsive to neuroendocrine stress signaling through the glucocorticoid receptor, and recent evidence with this sample and others shows that mitochondrial DNA copy number (mtDNAcn) is increased in adults with a history of early stress. No prior work has examined the role of NR3C1 methylation in the association between early life stress and mtDNAcn alterations.

Methods: Adult participants (n = 290) completed diagnostic interviews and questionnaires characterizing early stress and lifetime psychiatric symptoms. Medical conditions, active substance abuse, and prescription medications other than oral contraceptives were exclusionary. Subjects with a history of lifetime bipolar, obsessive-compulsive, or psychotic disorders were excluded; individuals with other forms of major psychopathology were included. Whole blood mtDNAcn was measured using qPCR; NR3C1 methylation was measured via pyrosequencing. Multiple regression and bootstrapping procedures tested NR3C1 methylation as a mediator of effects of early stress on mtDNAcn.

Results: The positive association between early adversity and mtDNAcn (p = .02) was mediated by negative associations of early adversity with NR3C1 methylation (p = .02) and NR3C1 methylation with mtDNAcn (p < .001). The indirect effect involving early adversity, NR3C1 methylation, and mtDNAcn was significant (95 % CI [.002, .030]).

Conclusions: NR3C1 methylation significantly mediates the association between early stress and mtDNAcn, suggesting that glucocorticoid receptor signaling may be a mechanistic pathway underlying mtDNAcn alterations of interest for future longitudinal work.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887859PMC
June 2020

Corrigendum to "Childhood maltreatment, behavioral adjustment, and molecular markers of cellular aging in preschool-aged children: A cohort study" [Psychoneuroendocrinology 107 (2019) 261-269].

Psychoneuroendocrinology 2019 Dec 8;110:104466. Epub 2019 Oct 8.

Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA. Electronic address:

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http://dx.doi.org/10.1016/j.psyneuen.2019.104466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848819PMC
December 2019

Childhood maltreatment, behavioral adjustment, and molecular markers of cellular aging in preschool-aged children: A cohort study.

Psychoneuroendocrinology 2019 09 15;107:261-269. Epub 2019 May 15.

Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA. Electronic address:

Objective: Childhood maltreatment is a major risk factor for the development of behavioral problems and poor physical and mental health. Accelerated cellular aging, through reduced telomere length and mitochondrial dysfunction, may be a mechanism underlying these associations.

Methods: Families with (nā€‰=ā€‰133) and without (nā€‰=ā€‰123) child welfare documentation of moderate-severe maltreatment in the past six months participated in this study. Children ranged in age from 3 to 5 years, were racially and ethnically diverse, and 91% qualified for public assistance. Structured record review and interviews were used to assess a history of maltreatment and other adversities. Telomere length and mitochondrial DNA copy number (mtDNAcn) were measured from saliva DNA using real-time PCR. Measures were repeated at a six-month follow-up assessment. Repeated measures general linear models were used to examine the effects of maltreatment and other adversities on telomere length and mtDNAcn over time.

Results: Maltreatment and other adverse experiences were significant positive predictors of both telomere length and mtDNAcn over time. Internalizing and externalizing behavior problems were also both significantly associated with telomere length, but only internalizing symptoms were associated with mtDNAcn.

Conclusions: This is the first study to show that mtDNAcn is altered in children with stress and trauma, and the findings are consistent with recent studies of adults. Surprisingly, children who experienced moderate-severe levels of maltreatment in the prior six months had longer telomeres, possibly reflecting compensatory changes in response to recent trauma. Telomere length and mtDNAcn were also associated with behavioral problems, suggesting that these measures of cellular aging may be causally implicated in the pathophysiology of stress-related conditions.
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http://dx.doi.org/10.1016/j.psyneuen.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839663PMC
September 2019

Synapsins regulate brain-derived neurotrophic factor-mediated synaptic potentiation and axon elongation by acting on membrane rafts.

Eur J Neurosci 2017 04 21;45(8):1085-1101. Epub 2017 Mar 21.

Department of Psychiatry and Human Behavior, Brown University, 171 Meeting Street, Room 187, Providence, RI, 02912, USA.

In neurons, intracellular membrane rafts are essential for specific actions of brain-derived neurotrophic factor (BDNF), which include the regulation of axon outgrowth, growth cone turning and synaptic transmission. Virtually, all the actions of BDNF are mediated by binding to its receptor, TrkB. The association of TrkB with the tyrosine kinase, Fyn, is critical for its localization to intracellular membrane rafts. Here, we show that synapsins, a family of highly amphipathic neuronal phosphoproteins, regulate membrane raft lipid composition and consequently, the ability of BDNF to regulate axon/neurite development and potentiate synaptic transmission. In the brains of mice lacking all synapsins, the expression of both BDNF and TrkB were increased, suggesting that BDNF/TrkB-mediated signaling is impaired. Consistent with this finding, synapsin-depleted neurons exhibit altered raft lipid composition, deficient targeting of Fyn to rafts, attenuated TrkB activation, and abrogation of BDNF-stimulated axon outgrowth and synaptic potentiation. Conversely, overexpression of synapsins in neuroblastoma cells results in corresponding reciprocal changes in raft lipid composition, increased localization of Fyn to rafts and promotion of BDNF-stimulated neurite formation. In the presence of synapsins, the ratio of cholesterol to estimated total phospholipids converged to 1, suggesting that synapsins act by regulating the ratio of lipids in intracellular membranes, thereby promoting lipid raft formation. These studies reveal a mechanistic link between BDNF and synapsins, impacting early development and synaptic transmission.
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http://dx.doi.org/10.1111/ejn.13552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450799PMC
April 2017

Association of telomere length and mitochondrial DNA copy number in a community sample of healthy adults.

Exp Gerontol 2015 Jun 3;66:17-20. Epub 2015 Apr 3.

Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, USA.

Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The present study examined the association between mitochondrial DNA (mtDNA) copy number and telomere length in a sample of medically healthy adults. Participants (total n=392) were divided into 4 groups based on the presence or absence of early life adversity and lifetime psychopathology: No Adversity/No Disorder, n=136; Adversity/No Disorder, n=91; No Adversity/Disorder, n=46; Adversity/Disorder, n=119. Telomere length and mtDNA copy number were measured using quantitative polymerase chain reaction. There was a positive correlation between mtDNA and telomere length in the entire sample (r=0.120, p<0.001) and in each of the four groups of participants (No Adversity/No Disorder, r=0.291, p=0.001; Adversity/No Disorder r=0.279, p=0.007; No Adversity/Disorder r=0.449, p=0.002; Adversity/Disorder, r=0.558, p<0.001). These correlations remained significant when controlling for age, smoking, and body mass index and establish an association between mtDNA and telomere length in a large group of women and men both with and without early adversity and psychopathology, suggesting co-regulation of telomeres and mitochondrial function. The mechanisms underlying this association may be important in the pathophysiology of age-related medical conditions, such as heart disease and cancer, as well as for stress-associated psychiatric disorders.
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http://dx.doi.org/10.1016/j.exger.2015.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459604PMC
June 2015

Alterations of Mitochondrial DNA Copy Number and Telomere Length With Early Adversity and Psychopathology.

Biol Psychiatry 2016 Jan 15;79(2):78-86. Epub 2015 Jan 15.

Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence.

Background: Telomere shortening and alterations of mitochondrial biogenesis are involved in cellular aging. Childhood adversity is associated with telomere shortening, and several investigations have shown short telomeres in psychiatric disorders. Recent studies have examined whether mitochondria might be involved in neuropsychiatric conditions; findings are limited and no prior work has examined this in relation to stress exposure.

Methods: Two-hundred ninety healthy adults provided information on childhood parental loss and maltreatment and completed diagnostic interviews. Participants were categorized into four groups based upon the presence or absence of childhood adversity and the presence or absence of lifetime psychopathology (depressive, anxiety, and substance use disorders). Telomere length and mitochondrial DNA (mtDNA) copy number were measured from leukocyte DNA by quantitative polymerase chain reaction.

Results: Childhood adversity and lifetime psychopathology were each associated with shorter telomeres (p < .01) and higher mtDNA copy numbers (p < .001). Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment. A history of substance disorders was also associated with significantly higher mtDNA copy numbers.

Conclusions: This study provides the first evidence of an alteration of mitochondrial biogenesis with early life stress and with anxiety and substance use disorders. We replicate prior work on telomere length and psychopathology and show that this effect is not secondary to medication use or comorbid medical illness. Finally, we show that early life stress and psychopathology are each associated with these markers of cellular aging.
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http://dx.doi.org/10.1016/j.biopsych.2014.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503518PMC
January 2016

Synapsin III: role in neuronal plasticity and disease.

Semin Cell Dev Biol 2011 Jun 30;22(4):416-24. Epub 2011 Jul 30.

Department of Psychiatry and Human Behavior, Brown University, BioMedical Center, 171 Meeting Street, Room 187, Providence, RI 02912, USA.

Synapsin III was discovered in 1998, more than two decades after the first two synapsins (synapsins I and II) were identified. Although the biology of synapsin III is not as well understood as synapsins I and II, this gene is emerging as an important factor in the regulation of the early stages of neurodevelopment and dopaminergic neurotransmission, and in certain neuropsychiatric illnesses. Molecular genetic and clinical studies of synapsin III have determined that its neurodevelopmental effects are exerted at the levels of neurogenesis and axonogenesis. In vitro voltammetry studies have shown that synapsin III can control dopamine release in the striatum. Since dopaminergic dysfunction is implicated in many neuropsychiatric conditions, one may anticipate that polymorphisms in synapsin III can exert pervasive effects, especially since it is localized to extrasynaptic sites. Indeed, mutations in this gene have been identified in individuals diagnosed with schizophrenia, bipolar disorder and multiple sclerosis. These and other findings indicate that the roles of synapsin III differ significantly from those of synapsins I and II. Here, we focus on the unique roles of the newest synapsin, and where relevant, compare and contrast these with the actions of synapsins I and II.
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http://dx.doi.org/10.1016/j.semcdb.2011.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185065PMC
June 2011

The correlation between rates of cancer and autism: an exploratory ecological investigation.

PLoS One 2010 Feb 23;5(2):e9372. Epub 2010 Feb 23.

Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, United States of America.

Background: Autism is associated with high rates of genomic aberrations, including chromosomal rearrangements and de novo copy-number variations. These observations are reminiscent of cancer, a disease where genomic rearrangements also play a role. We undertook a correlative epidemiological study to explore the possibility that shared risk factors might exist for autism and specific types of cancer.

Methodology/principal Findings: To determine if significant correlations exist between the prevalence of autism and the incidence of cancer, we obtained and analyzed state-wide data reported by age and gender throughout the United States. Autism data were obtained from the U.S. Department of Education via the Individuals with Disabilities Education Act (IDEA) (2000-2007, reported annually by age group) and cancer incidence data were obtained from the Centers for Disease Control and Prevention (CDC) (1999-2005). IDEA data were further subdivided depending on the method used to diagnose autism (DSM IV or the Code of Federal Regulations, using strict or expanded criteria). Spearman rank correlations were calculated for all possible pairwise combinations of annual autism rates and the incidence of specific cancers. Following this, Bonferroni's correction was applied to significance values. Two independent methods for determining an overall combined p-value based on dependent correlations were obtained for each set of calculations. High correlations were found between autism rates and the incidence of in situ breast cancer (p < or = 10(-10), modified inverse chi square, n = 16) using data from states that adhere strictly to the Code of Federal Regulations for diagnosing autism. By contrast, few significant correlations were observed between autism prevalence and the incidence of 23 other female and 22 male cancers.

Conclusions: These findings suggest that there may be an association between autism and specific forms of cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826417PMC
February 2010

Childhood maltreatment and telomere shortening: preliminary support for an effect of early stress on cellular aging.

Biol Psychiatry 2010 Mar 14;67(6):531-4. Epub 2009 Oct 14.

Mood Disorders Research Program, Butler Hospital, Providence, Rhode Island, USA.

Background: Psychological stress and trauma are risk factors for several medical and psychiatric illnesses. Recent studies have implicated advanced cellular aging as a potential mechanism of this association. Telomeres, DNA repeats that cap the ends of chromosomes and promote stability, shorten progressively with each cell division; their length is a marker of biological aging. Based on previous evidence linking psychosocial stress to shorter telomere length, this study was designed to evaluate the effect of childhood adversity on telomere length.

Methods: Thirty-one adults with no current or past major Axis I psychiatric disorder participated. Subjects reported on their history of childhood maltreatment and telomere length was measured from DNA extracted from frozen whole blood using quantitative polymerase chain reaction.

Results: Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment. This finding was not due to effects of age, sex, smoking, body mass index, or other demographic factors. Analysis of subscales showed that both physical neglect and emotional neglect were significantly linked to telomere length.

Conclusions: These results extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote stressful experiences in childhood and suggest that childhood maltreatment could influence cellular aging.
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http://dx.doi.org/10.1016/j.biopsych.2009.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853238PMC
March 2010

Telomerase levels in schizophrenia: a preliminary study.

Schizophr Res 2008 Dec 1;106(2-3):242-7. Epub 2008 Oct 1.

Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.

We previously demonstrated that telomere length was markedly reduced in peripheral blood lymphocytes from individuals with schizophrenia. Since reduced telomere length can be caused by decreased telomerase activity, we quantitated basal telomerase activity in peripheral blood lymphocytes derived from individuals with schizophrenia (n=53), unaffected relatives (n=31) and unrelated controls (n=59). Telomerase activity varied greatly among individuals, suggesting that this enzymatic activity is affected by various factors. We observed a nominally significant decrease in telomerase activity among individuals with schizophrenia compared to unaffected individuals (unaffected relatives and unrelated controls). Further studies are needed to investigate the role of telomerase in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2008.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613190PMC
December 2008

Strict regulation of gene expression from a high-copy plasmid utilizing a dual vector system.

Protein Expr Purif 2008 Jul 26;60(1):53-7. Epub 2008 Mar 26.

Brown University, Department of Psychiatry and Human Behavior, Division of Biology and Medicine, 171 Meeting Street, Room 187, Box G-B187, Providence, RI 02912, USA.

High-copy plasmids are useful for producing large quantities of plasmid DNA, but are generally inadequate for tightly regulating gene expression. Attempts to suppress expression of genes on high-copy plasmids often results in residual or "leaky" production of protein. For stringent regulation of gene expression, it is often necessary to excise the gene of interest and subclone it into a low-copy plasmid. Here, we report a dual plasmid technique that enables tight regulation of gene expression driven by the lac promoter in a high-copy vector. A series of plasmids with varying copies of the lacI(q) gene have been constructed to permit titration of the LacI protein. When a high-copy plasmid is transformed along with the appropriate lacI(q)-containing plasmid, tight gene regulation is achieved, thus eliminating the need to subclone genes into low-copy plasmids. In addition, we show that this dual plasmid technique enables high-copy gene expression of a protein lethal to Escherichia coli, the ccdB protein. In principle, this technique can be applied to any high-copy plasmid containing the popular pUC replication of origin and provides an easier means of obtaining rigid control over gene expression.
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http://dx.doi.org/10.1016/j.pep.2008.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442401PMC
July 2008

Early involvement of synapsin III in neural progenitor cell development in the adult hippocampus.

J Comp Neurol 2008 Apr;507(6):1860-70

Nathan Kline Institute for Psychiatric Research and the Department of Psychiatry, New York University School of Medicine, Orangeburg, New York 10962, USA.

Synapsin III is a synaptic vesicle-associated protein that is expressed in cells of the subgranular layer of the hippocampal dentate gyrus, a brain region known to sustain substantial levels of neurogenesis into adulthood. Here we tested the hypothesis that synapsin III plays a role in adult neurogenesis with synapsin III knockout and wild-type mice. Immunocytochemistry of the adult hippocampal dentate gyrus revealed that synapsin III colocalizes with markers of neural progenitor cell development (nestin, PSA-NCAM, NeuN, and Tuj1) but did not colocalize with markers of mitosis (Ki67 and PCNA). Because neurogenesis consists of a number of stages, the proliferation, survival, and differentiation of neural progenitor cells were systematically quantitated in the hippocampal dentate gyrus of adult synapsin III knockout and wild-type mice. We found a 30% decrease in proliferation and a 55% increase in survival of neural progenitor cells in synapsin III knockout mice. We also observed a 6% increase in the number of neural progenitor cells that differentiated into neurons. No difference in the volume of the dentate gyrus was observed between synapsin III knockout and wild-type mice. Collectively, our results demonstrate a novel role for synapsin III in regulating the proliferation of neural progenitor cells in the adult hippocampal dentate gyrus. These findings suggest a distinct function for this synaptic vesicle protein, in addition to its role in neurotransmission.
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http://dx.doi.org/10.1002/cne.21643DOI Listing
April 2008

BDNF Val66Met variant and age of onset in schizophrenia.

Am J Med Genet B Neuropsychiatr Genet 2008 Jun;147B(4):505-6

Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.

Brain-derived neurotrophic factor (BDNF) has been advanced as a candidate gene for schizophrenia by virtue of its effects on neurotransmitter systems that are dysregulated in psychiatric disorder and its involvement in the response to antipsychotic drugs. The extensively examined BDNF gene Val66Met (or rs6265) variant has been associated with schizophrenia, and studies have linked this polymorphism to brain morphology, cognitive function, and psychiatric symptoms in schizophrenia. Moreover the BDNF Val66Met variant has been reported to be associated with age of onset in schizophrenia. Genotyping of African-American subjects with schizophrenia for five BDNF coding region single nucleotide polymorphisms revealed variance only at the Val66Met allele. The results of statistical analyses indicate a relationship between the BDNF Val66Met genotype and the ages of first psychiatric hospitalization and first schizophrenia symptoms.
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http://dx.doi.org/10.1002/ajmg.b.30619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2396782PMC
June 2008

Reduction of synapsin III in the prefrontal cortex of individuals with schizophrenia.

Schizophr Res 2007 Aug 30;94(1-3):366-70. Epub 2007 May 30.

Nathan Kline Institute for Psychiatric Research and Department of Psychiatry, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, New York 10962, United States.

We analyzed the expression of a presynaptic protein, synapsin III, in individuals with schizophrenia. Since levels of synapsin III were previously found to be significantly reduced in the hippocampus of individuals with schizophrenia, we examined another brain region believed to be a major locus of dysfunction in schizophrenia, the dorsolateral prefrontal cortex (DLPFC). Western blot analyses using tissue obtained from the Stanley Foundation Neuropathology Consortium revealed that synapsin III levels were significantly decreased in the DLPFC of individuals with schizophrenia compared to controls. These findings are consistent with growing evidence of presynaptic abnormalities and prefrontal cortical dysfunction in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2007.04.016DOI Listing
August 2007

Protein expression profiling of postmortem brain in schizophrenia.

Schizophr Res 2006 Jun 19;84(2-3):204-13. Epub 2006 Apr 19.

Ciphergen Biosystems, Inc., 6611 Dumbarton Circle, Fremont, CA 94555, USA.

Surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) enables the sensitive, high-throughput protein profiling of complex biological mixtures. In combination with bioinformatics, this technology has the potential to identify combinations of spectral peaks that can differentiate individuals with a particular disease from normal controls. SELDI-TOF-MS was used to screen postmortem tissue derived from the dorsolateral prefrontal cortex of individuals with schizophrenia (n = 34) and matched controls (n = 35), obtained from the Stanley Foundation Neuropathology Consortium. Tissue samples were homogenized in urea buffer, applied to four different chip arrays which possess different chromatographic surfaces, and analyzed using the Ciphergen ProteinChip Biomarkers System (Model PBS II). Protein expression profiles of the schizophrenia and control groups were compared and analyzed using the Ciphergen Express (CE) and Biomarker Patterns Software (BPS) package. We detected several protein peaks whose intensities differed between the schizophrenia and control groups to a highly significant degree. A combination of these peaks was capable of distinguishing between schizophrenia and controls with a sensitivity and specificity of about 70%. The classification model that distinguished schizophrenia from controls was complex, suggesting that the biochemical abnormalities underlying schizophrenia are heterogeneous. Our results suggest that SELDI-TOF-MS has the potential for distinguishing individuals with schizophrenia from normal controls and may eventually lead to a better understanding of the classification, diagnosis and pathogenesis of this disorder.
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http://dx.doi.org/10.1016/j.schres.2006.02.016DOI Listing
June 2006

Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons.

Proc Natl Acad Sci U S A 2006 Jan 22;103(1):21-6. Epub 2005 Dec 22.

Howard Hughes Medical Institute and Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.

Although fucose-alpha(1-2)-galactose [Fucalpha(1-2)Gal] carbohydrates have been implicated in cognitive processes such as long-term memory, the molecular mechanisms by which these sugars influence neuronal communication are not well understood. Here, we present molecular insights into the functions of Fucalpha(1-2)Gal sugars, demonstrating that they play a role in the regulation of synaptic proteins and neuronal morphology. We show that synapsins Ia and Ib, synapse-specific proteins involved in neurotransmitter release and synaptogenesis, are the major Fucalpha(1-2)Gal glycoproteins in mature cultured neurons and the adult rat hippocampus. Fucosylation has profound effects on the expression and turnover of synapsin in cells and protects synapsin from degradation by the calcium-activated protease calpain. Our studies suggest that defucosylation of synapsin has critical consequences for neuronal growth and morphology, leading to stunted neurite outgrowth and delayed synapse formation. We also demonstrate that Fucalpha(1-2)Gal carbohydrates are not limited to synapsin but are found on additional glycoproteins involved in modulating neuronal architecture. Together, our studies identify important roles for Fucalpha(1-2)Gal sugars in the regulation of neuronal proteins and morphological changes that may underlie synaptic plasticity.
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http://dx.doi.org/10.1073/pnas.0503381102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1324972PMC
January 2006

A rare polymorphism affects a mitogen-activated protein kinase site in synapsin III: possible relationship to schizophrenia.

Biol Psychiatry 2004 Jan;55(2):118-25

Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA.

Background: Synapsin III plays a role in neuronal plasticity and maps to chromosome 22q12-13, a region suggested to be linked to schizophrenia. To determine if synapsin III plays a role in this disease, we searched for polymorphisms in this gene in patients with schizophrenia and controls.

Methods: The synapsin III gene was initially sequenced from 10 individuals with schizophrenia to identify polymorphisms. Association analysis was then performed using 118 individuals with schizophrenia and 330 population controls. Synapsin III expression was studied by immunoblot analyses, and phosphorylation sites were mapped by sequencing trypsin-digested synapsin III fragments phosphorylated with phosphorus-32.

Results: A rare, missense polymorphism, S470N, was identified in the synapsin III gene and appeared more frequently in individuals with schizophrenia than in controls (p =.0048). The site affected by the polymorphism, Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. Phosphorylation at Ser470 was increased during neonatal development and in response to neurotrophin-3 in cultured hippocampal neurons.

Conclusions: Our observations suggest an association of a rare polymorphism in synapsin III with schizophrenia, but further studies will be required to clarify its role in this disease.
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http://dx.doi.org/10.1016/j.biopsych.2003.07.002DOI Listing
January 2004

Effect of protein phosphorylation on neurite outgrowth in cultured embryonic Xenopus spinal neurons.

Neurosignals 2003 Jan-Feb;12(1):45-52

Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, N.Y. 10962, USA.

Intracellular signaling pathways involved in neurite outgrowth have been extensively studied in a variety of cell systems. While most of these studies utilized continuous neuronal-like cell lines, fewer studies have been conducted in primary neuronal culture. One primary culture system that has recently been used to dissect the signaling pathways involved in axon guidance consists of spinal neurons derived from embryonic Xenopus laevis. In this study, we used Xenopus to study neurite outgrowth by treating neuronal cultures with pharmacological agents that activate or inhibit various protein kinases or that inhibit protein phosphatases. We found that agents which affected signaling via cAMP-dependent protein kinase, calmodulin, cyclin-dependent kinase 5, or protein phosphatases had effects on Xenopus neurite outgrowth that were similar to those reported in other primary neurons or in neuronal-like cell lines. However, agents which affected protein kinase C signaling had effects on Xenopus neurite outgrowth that were distinct from those reported in neuronal-like cell lines. Although continuous cell lines have several advantages for the dissection of signaling pathways involved in neurodevelopment, these observations underscore the importance of also using primary neurons to examine these pathways.
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http://dx.doi.org/10.1159/000068916DOI Listing
May 2003

Expression of synapsin III in nerve terminals and neurogenic regions of the adult brain.

J Comp Neurol 2002 Dec;454(2):105-14

The John B Pierce Laboratory, Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

We have examined the distribution of synapsin III in the adult mouse brain. Expression of synapsin III was observed in puncta throughout the brain, but demonstrated greater regional variation than that of synapsins I or II. This punctate staining is typical for synaptic vesicle proteins located at nerve terminals. These findings are also consistent with the well-established role for synapsins in regulating neurotransmitter release. However, unexpectedly, synapsin III was also highly expressed in the cell body and processes of immature neurons in neurogenic regions of the adult brain, such as the hippocampal dentate gyrus, rostral migratory stream, and olfactory bulb. Many synapsin III-positive neurons also reacted with an antibody directed toward polysialylated-neuronal cell adhesion molecule, a marker of immature, migrating neurons. These results suggest that synapsin III may also play a role in adult neurogenesis.
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http://dx.doi.org/10.1002/cne.10417DOI Listing
December 2002

A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth.

Nat Neurosci 2002 May;5(5):431-7

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). We show here, using both Xenopus laevis embryonic neuronal culture and intact X. laevis embryos, that the nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue. Expression of a mutated form of synapsin that prevents phosphorylation at this site, or introduction of phospho-specific antibodies directed against this site, decreased basal and dibutyryl cAMP-stimulated neurite outgrowth. Expression of a mutation mimicking constitutive phosphorylation at this site increased neurite outgrowth, both under basal conditions and in the presence of a PKA inhibitor. These results provide a potential molecular approach for stimulating neuron regeneration, after injury and in neurodegenerative diseases.
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http://dx.doi.org/10.1038/nn840DOI Listing
May 2002