A new mouse model of pediatric autoimmune neuropsychiatric disorders

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Original Article

Molecular Psychiatry advance online publication 11 August 2009; doi: 10.1038/mp.2009.77

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

K Yaddanapudi 1,2, M Hornig 1,2, R Serge 1, J De Miranda 1, A Baghban 1, G Villar 1 and W I Lipkin 1

1 Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

Correspondence: Dr M Hornig, Center for Infection and Immunity, Mailman School of Public Health,Columbia University, 722 W 168th Street, New York, NY 10032, USA. E-mail: mh2092@columbia.edu

2 These authors contributed equally to this work.

Received 25 February 2009; Revised 11 June 2009; Accepted 15 June 2009; Published online 11 August 2009.

Abstract

Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood–brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.

Brains of psychopaths are different

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Original Article

Molecular Psychiatry advance online publication 9 June 2009; doi: 10.1038/mp.2009.40
Altered connections on the road to psychopathy

M C Craig1,2, M Catani1,2, Q Deeley1, R Latham1, E Daly1, R Kanaan3, M Picchioni3, P K McGuire3, T Fahy4 and D G M Murphy1

1. Section of Brain Maturation, Institute of Psychiatry, De Crespigny Park, London, UK
2. Natbrainlab, Institute of Psychiatry, De Crespigny Park, London, UK
3. Section of Neuroimaging, Institute of Psychiatry, De Crespigny Park, London, UK
4. Department of Forensic Mental Health Science, Institute of Psychiatry, De Crespigny Park, London, UK

Correspondence: Dr MC Craig, Psychological Medicine, Institute of Psychiatry, PO50, 16 De Crespigny Park, Denmark Hill, London SE5 8AF, UK. E-mail: m.craig@iop.kcl.ac.uk

Received 7 August 2008; Revised 25 February 2009; Accepted 13 April 2009; Published online 9 June 2009.

Abstract

Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of greater than or equal to25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003),>post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala–OFC limbic network underpin the neurobiological basis of psychopathy.

BDNF and depression: the plot thickens

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Original Article

Molecular Psychiatry advance online publication 21 July 2009; doi: 10.1038/mp.2009.67

Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis

MPOpen

D Taliaz, N Stall, D E Dar and A Zangen

Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Correspondence: Dr A Zangen, Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: a.zangen@weizmann.ac.il

Received 19 December 2008; Revised 29 April 2009; Accepted 15 June 2009; Published online 21 July 2009.

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Abstract

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.

Biomarkers for Post-partum Depression

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Original Article

Molecular Psychiatry advance online publication 7 July 2009; doi: 10.1038/mp.2009.65

Blood mononuclear cell gene expression signature of postpartum depression

R H Segman1, T Goltser-Dubner1,5, I Weiner2,5, L Canetti1, E Galili-Weisstub1, A Milwidsky3,4, V Pablov1, N Friedman2 and D Hochner-Celnikier3,4

1. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2. School of Computer Science and Engineering, Hebrew University, Jerusalem, Israel

3. Child & Adolescent Psychiatry Unit, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

4. Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Correspondence: Dr RH Segman, Department of Psychiatry, Hadassah-Hebrew University Medical Center, POB 24035 Mount Scopus, Jerusalem 91240, Israel. E-mail: ronense@ekmd.huji.ac.il

5These two authors contributed equally to this work.

Received 25 November 2008; Revised 30 April 2009; Accepted 9 June 2009; Published online 7 July 2009.

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Abstract

In sorrow thou shalt bring forth children (Genesis 3:16) seems as relevant today, with one of seven mothers afflicted by a depressive episode, constituting the most common medical complication after delivery. Why mothers are variably affected by mood symptoms postpartum remains unclear, and the pathogenesis and early molecular indicators of this divergent outcome have not been described. We applied a case–control design comparing differential global gene expression profiles in blood mononuclear cells sampled shortly after delivery at the time of inception of postpartum depression (PD). Nine antidepressant naive mothers showing high depressive scores and developing a persisting major depressive episode with postpartum onset were compared with 10 mothers showing low depressive scores and no depressive symptoms on prospective follow-up. A distinctive gene expression signature was observed after delivery among mothers with an emergent PD, with a significant overabundance of transcripts showing a high-fold differential expression between groups, and correlating with depressive symptom severity among all mothers. Early expression signatures correctly classified the majority of PD patients and controls. Those developing persisting PD exhibit a relative downregulation of transcription after delivery, with differential immune activation, and decreased transcriptional engagement in cell proliferation, and DNA replication and repair processes. Our data provide initial evidence indicating that blood cells sampled shortly after delivery may harbor valuable prognostic information for identifying the onset of persisting PD. Some of the informative transcripts and pathways may be implicated in the differential vulnerability that underlies depression pathogenesis.