Am J Hum Genet 2002 Sep;71(3):651-5
The brain-derived neurotrophic factor gene confers susceptibility
to bipolar disorder: evidence from a family-based association
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL.
Neurogenetics Section, Centre for Addiction and Mental Health, Department of
Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada.
Bipolar disorder (BP) is a severe psychiatric disease, with a strong genetic
component, that affects 1% of the population worldwide and is characterized by
recurrent episodes of mania and depression. Brain-derived neurotrophic factor
(BDNF) has been implicated in the pathogenesis of mood disorders, and the aim of
the present study was to test for the presence of linkage disequilibrium between
two polymorphisms in the BDNF gene and BP in 283 nuclear families. Family-based
association test (FBAT) results for the dinucleotide repeat (GT)(N) polymorphism
at position -1040 bp showed that allele A3 was preferentially transmitted to the
affected individuals (Z=2.035 and P=.042). FBAT results for the val66met SNP
showed a significant association for allele G (Z=3.415 and P=.00064).
Transmission/disequilibrium test (TDT) haplotype analysis showed a significant
result for the 3-G allele combination (P=.000394), suggesting that a DNA variant in
the vicinity of the BDNF locus confers susceptibility to BP. Given that there is no
direct evidence that either of the polymorphisms we examined alters function, it is
unlikely that the actual risk-conferring allele is from these two sites. Rather, the
causative site is likely nearby and in linkage disequilibrium with the 3-G haplotype
that we have identified.
Mol Psychiatry 2002;7(6):579-93
Family-based association study of 76 candidate genes in bipolar
disorder: BDNF is a potential risk locus. Brain-derived neutrophic
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S,
Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES.
Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit,
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Identification of the genetic bases for bipolar disorder remains a challenge for the
understanding of this disease. Association between 76 candidate genes and bipolar
disorder was tested by genotyping 90 single-nucleotide polymorphisms (SNPs) in
these genes in 136 parent-proband trios. In this preliminary analysis, SNPs in two
genes, brain-derived neurotrophic factor (BDNF) and the alpha subunit of the
voltage-dependent calcium channel were associated with bipolar disorder at the
P<0.05 level. In view of the large number of hypotheses tested, the two nominally
positive associations were then tested in independent populations of bipolar patients
and only BDNF remains a potential risk gene. In the replication samples, excess
transmission of the valine allele of amino acid 66 of BDNF was observed in the
direction of the original result in an additional sample of 334 parent-proband trios
(T/U=108/87, P=0.066). Resequencing of 29 kb surrounding the BDNF gene
identified 44 additional SNPs. Genotyping eight common SNPs identified three
additional markers transmitted to bipolar probands at the P < 0.05 level. Strong LD
was observed across this region and all adjacent pairwise haplotypes showed excess
transmission to the bipolar proband. Analysis of these haplotypes using TRANSMIT
revealed a global P value of 0.03. A single haplotype was identified that is shared by
both the original dataset and the replication sample that is uniquely marked by both
the rare A allele of the original SNP and a novel allele 11.5 kb 3'. Therefore, this
study of 76 candidate genes has identified BDNF as a potential risk allele that will
require additional study to confirm.
Mol Psychiatry 2002;7 Suppl 1:S29-34
Synaptic plasticity and mood disorders.
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut
Mental Health Center, Yale University School of Medicine, New Haven, CT, USA.
Recent studies demonstrate that the molecular elements known to regulate neuronal
plasticity in models of learning and memory are also involved in the actions of drugs
used for the treatment of depression and bipolar disorder. This includes
up-regulation of transcription factors, such as the cAMP response element binding
protein and neurotrophic factors, such as brain derived neurotrophic factor. These
findings raise the possibility that regulation of neural plasticity in specific neuronal
circuits is integrally involved in the therapeutic intervention of mood disorders.
Atypical antipsychotic drugs, including clozapine and olanzapine, are also effective
for the treatment of bipolar disorder, and are used as add-on medication for
unipolar depression. The possibility that these atypical antipsychotic drugs also
influence the molecular determinants of synaptic plasticity that are involved in the
response to drugs used for the treatment of mood disorders, is discussed.
Biol Psychiatry 2001 Aug 15;50(4):260-5
Increased hippocampal BDNF immunoreactivity in subjects treated
with antidepressant medication.
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT.
Department of Psychiatry and Behavioral Neuroscience, McMaster University,
Hamilton, Ontario, Canada.
BACKGROUND: The cAMP signaling pathway, and its downstream neurotrophic
factor BDNF, are major targets of antidepressant medications. Abnormalities in
this pathway have previously been reported in postmortem brain of subjects with
mood disorders. This study was designed to test whether the diagnosis of a mood
disorder, or treatment with an antidepressant or mood stabilizer was associated
with changes in hippocampal BDNF in postmortem brain. METHODS: Frozen
postmortem anterior hippocampus sections were obtained from the Stanley
Foundation Neuropathology Consortium. Tissue from subjects with major
depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects
were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF
expression was found in dentate gyrus, hilus and supragranular regions in subjects
treated with antidepressant medications at the time of death, compared with
antidepressant-untreated subjects. Furthermore, there was a trend toward
increased BDNF expression in hilar and supragranular regions in depressed subjects
treated with antidepressants, compared with the subjects not on these medications
at the time of death. CONCLUSIONS: These findings are consistent with recent
studies measuring CREB levels in this same subject sample, and support current
animal and cellular models of antidepressant function.
Biol Psychiatry 2000 Oct 15;48(8):766-77
Postmortem studies in mood disorders indicate altered numbers of
neurons and glial cells.
Laboratory of Quantitative Neuroanatomy, Department of Psychiatry and Human
Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
The influence of stress and glucocorticoids on neuronal pathology has been
demonstrated in animal and clinical studies. It has been proposed that
stress-induced changes in the hippocampus may be central to the development of
depression in genetically vulnerable individuals. New evidence implicates the
prefrontal cortex (PFC) in addition to the hippocampus as a site of neuropathology
in depression. The PFC may be involved in stress-mediated neurotoxicity because
stress alters PFC functions and glucocorticoid receptors, the PFC is directly
interconnected with the hippocampus, and metabolic alterations are present in the
PFC in depressed patients. Postmortem studies in major depression and bipolar
disorder provide the first evidence for specific neuronal and glial histopathology in
mood disorders. Three patterns of morphometric cellular changes are noted: cell loss
(subgenual PFC), cell atrophy (dorsolateral PFC and orbitofrontal cortex), and
increased numbers of cells (hypothalamus, dorsal raphe nucleus). The relevance of
cellular changes in mood disorders to stress and prolonged PFC development and a
role of neurotrophic/neuroprotective factors are suggested, and a link between
cellular changes and the action of therapeutic drugs is discussed. The precise
anatomic localization of dysfunctional neurons and glia in mood disorders may reveal
cortical targets for novel antidepressants and mood stabilizers.
Psychopharmacol Bull 2001 Spring;35(2):5-49
Impairments of neuroplasticity and cellular resilience in severe
mood disorders: implications for the development of novel
Manji HK, Duman RS.
Laboratory of Molecular Pathophysiology,
NIMH, Building 49, Room B1EE16, 49
Convent Dr MSC 4405, Bethesda, MD 20892-4405, USA.
Mood disorders have traditionally been conceptualized as neurochemical disorders,
but there is now evidence from a variety of sources demonstrating regional
reductions in central nervous system (CNS) volume, as well as reductions in the
numbers and/or sizes of glia and neurons in discrete brain areas. Although the
precise cellular mechanisms underlying these morphometric changes remain to be
fully elucidated, the data suggests that mood disorders are associated with
impairments of structural plasticity and cellular resilience. Recent preclinical and
clinical studies have shown that signaling pathways involved in regulating cell survival
and cell death are long-term targets for the actions of antidepressants and mood
stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of
factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP
kinases, and may thus bring about some of their delayed long term beneficial
effects via underappreciated neurotrophic effects. The future development of
treatments that more directly target molecules involved in critical CNS cell survival
and cell death pathways thus hold promise as novel, improved long-term treatments
for mood disorders.
Med Hypotheses 2002 Aug;59(2):154-8
Schizophrenia and other mental disorders require long-term
Institute of Immunology, Klinikum Innenstadt, University of Munich, Goethestrasse
31, 80336 Munich, Germany.
Many different microbial factors seem to contribute to the pathogenesis of
schizophrenic and other psychiatric disorders. Activation of all T lymphocytes
reactivates those downregulated by low-grade chronic infections and restores
equilibrium in immune cell subpopulations. Different immune cell subpopulations
express different neurotrophin receptors and produce different cytokines,
particularly brain-derived neurotrophin (BDNF) and neurotrophin 3 (NT3) [M.
Besser, R. Wank, J. Immunol. 162 (1998) 6303-6306] that appear to play a key role
in schizophrenic and bipolar disorders [E. Jonsson, S. Brene, X.R. Zhang, et al., Acta
Psychiatr. Scand. 95 (1997) 414-419; R.S. Duman, Arch. Gen. Psychiatry 54 (1997)
597-606; J.A. Siuciak, D.R. Lewis, S.J. Wiegand, R.M. Lindsay, Pharmacol. Biochem. Be
56 (1997) 131-137]. The hypothesis that adoptive immunotherapy is effective in
psychiatric disorders will be supported by three case reports, in a patient with
bipolar disorder, a patient with schizophrenia, and a patient with autism.
Family-Based Association Study Of 76 Candidate Genes In
Bipolar Disorder: BDNF Is A Potential Risk Locus
August 6, 2002
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.