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Brain-derived neurotrophic factor (BDNF): From maternal deprivation to manic depressive illness

Molecular Psychiatry

These results are presented in two articles (accompanied by an editorial) appearing in the forthcoming issue of Molecular Psychiatry (Nature Publishing Group):

ARTICLE (1): "Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus"

AUTHORS: M Roceri, W Hendricks, G Racagni, BA Ellenbroek and MA Riva

Center for Neuropharmacology, Department Pharmacological Sciences and Center of Excellence for Neurodegenerative Disorders, University of Milan, Milan, Italy; Department of Psychoneuropharmacology, University of Nijmegen, Nijmegen, The Netherlands: I.R.C.C.S. San Giovanni di Dio-Fatebenefratelli, Brescia, Italy

Over the last years, several lines of investigation have suggested that adverse life events during neuronal maturation can be critical for brain development thus producing persistent changes in its function and increasing the vulnerability to psychiatric disorders. Such vulnerability is related to the coping ability under challenging situation, such as stress, which represent and important precipitating factor in psychiatric diseases. Brain derived neurotrophic factor (BDNF) is a trophic protein that plays an important role in regulating neuronal function and plasticity. In a study conducted on rats, the authors have used maternal deprivation (MD) on postnatal day 9, an experimental paradigm that recapitulates many features of schizophrenia, in order to investigate long-term effects of early adverse life situation on brain function. They found that, as adult, MD animals show reduced expression of BDNF and glutamate NMDA receptor subunits, which are important players in cellular plasticity. These changes occur specifically in the hippocampus, a region important for cognition, and are only observed in adult animals.

The study, published in the August issue of Molecular Psychiatry, provides evidence for the presence of anatomically-defined molecular changes in the brain following exposure to adverse experience early in life. Although the study was conducted in rodents, it emphasizes the vulnerability of the brain to stressful condition during development. This work might contribute to understanding the molecular mechanisms that underlie brain vulnerability for psychiatric disorders and ultimately allow the identification of novel targets for the cure of psychiatric disorders that, to some extent, may be associated to an impairment in brain plasticity.

Citation source: Molecular Psychiatry 2002 Volume 7, number 6, pages 609-616.

For further information on this work, please contact Dr. MA Riva, Center of Neuropharmacology, Department Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy; phone: +39-02-85358334; FAX: +39-02-85358278; e-mail:

ARTICLE (2): "Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus"

AUTHORS: P Sklar, SB Gabriel, MG McInnis, P Bennett, Y-M Lim, G Tsan, S Schaffner, G Kirov, I Jones, M Owen, N Craddock, JR DePaulo and ES Lander

Department of Psychiatry, Psychiatric and Neurodevelopmental Genetic Unit, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Whitehead Institute/MIT Center for Genome Research, Cambridge, MA, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, UK; Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

Bipolar disorder (also known as manic depressive illness) is an episodic illness characterized by extreme disturbances in mood, including mania and depression. Family and twin studies have demonstrated a strong genetic basis for this disease but classical linkage studies - studies of inheritance patterns within families - have not found conclusive evidence for any one gene. Several studies have implicated various genes as culprits, although a definitive genetic cause does not exist.

Scientists have long considered the possibility that bipolar disorder is a complex disease, caused by several genes, each of which exerts a modest increase in relative risk in the population. Such types of risks are difficult to discover by linkage analysis, which typically focuses on extended families. Complex genetic diseases may best be dissected by so-called "association" studies, which analyze DNA from multiple large groups of patients in the general population and detects the effect of a SNP - a single letter variation in a gene - on a disease risk.

In this study, scientists undertook a systematic approach, identifying from the literature 76 candidate genes previously implicated in bipolar disorder and then identifying the SNPs in these genes. Using high-throughput genotyping technology at the Whitehead Genome Center, they then analyzed the patterns of inheritance of these SNPs from parents to their children with bipolar disorder. They found that a single SNP that causes an amino acid change in the BDNF protein is associated with bipolar disorder. This SNP is part of a larger haplotype - a set of SNPs that travel together - that resides on BDNF and seems to be the only one associated with an increased risk for bipolar illness. This pattern of risk was not found for any of the other 75 candidate genes they studied.

"Our study of 76 genes has narrowed down the search to BDNF but further studies will need to confirm our results," says Pamela Sklar, first author and researcher at the Whitehead and Psychiatric and Neurodevelopmental Genetics Unit at MGH.

BDNF is a gene found on chromosome 11 and belongs to a family of so-called neurotrophins - nerve chemicals that promote the growth and survival of neurons.


Citation source: Molecular Psychiatry 2002 Volume 7, number 6, pages 579-593.

For further information on this work, please contact Dr. P Sklar, Whitehead Institute/MIT Center for Genome Research, One Kendall Square, Building 300, Cambridge, MA 02139, USA; phone (617) 258-5000; e-mail:

Molecular Psychiatry is published by the Nature Publishing Group.

Editor: Julio Licinio, M.D.; phone: +1 310 825-7113; FAX: +1 310 206-6715; e-mail:

For a copy of these articles and accompanying editorial, please contact Frank Sissingh, editorial assistant, e-mail:


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