Schizophrenia and neurotrophin‐3 alleles

Abstract

Studies of brain anatomy and premorbid functioning indicate that schizophrenia may be of neurodevelopmental origin. In the neurotrophic factor neurotrophin-3 (NT-3) gene, the A3/147-bp allele in a dinucleotide repeat polymorphism located in the promoter region was found to be associated with schizophrenia in a Japanese study. Another NT-3 polymorphism (Glu63Gly) indicated an association with schizophrenic patients with a putative neurodevelopmental form of the disease. We examined Swedish schizophrenic patients (n = 109) and control subjects (n = 78) for the same two NT-3 polymorphisms, as well as a third silent exonic polymorphism (at Pro55). No significant difference was found between the two groups. However, in a meta-analysis including the present and previous studies of Caucasian subjects, the A3/147-bp allele frequency was found to be significantly higher in the schizophrenic patients. In the present study, carriers of the A3/147 bp allele tended to have an earlier age of onset and to display more extrapyramidal symptoms. In the silent exonic polymorphism (at Pro55), female schizophrenic patients had higher adenine and lower guanine allele frequencies than control female subjects. Together with previous studies, the results provide some support for an association between the NT-3 gene and certain forms of schizophrenia. This warrants further investigation of NT-3 and other neurotrophic factors with additional polymorphisms and larger patient samples.

BDNF in schizophrenia, depression and corresponding animal models

“…A genetic link between neurotrophins and schizophrenia is supported by the evidence that polymorphisms of the NT-3 and BDNF genes are associated with schizophrenia. [7][8][9] Lastly, findings that BDNF is decreased by factors correlated with first episode onset, such as stress 59,21 and estrogen withdrawal, 60 are also consistent with the putative BDNF role in schizophrenia. Interestingly, these stress-induced decreases in BDNF are blocked by 5-HT2 receptor antagonists, a receptor binding property of many neuroleptics.…”

“…Studies on post-mortem Human Decreased BDNF concentrations in cortical areas and hippocampus of schizophrenic patients 4 Reduction of TrkB and BDNF-positive neurons in CNS 5 and BDNF in the serum 6 of schizophrenics Polymorphisms of BDNF gene associated with schizophrenia [7][8][9] Animal models…”

“…Chronic administration of antidepressants increases BDNF expression in the hippocampus 17,18 BDNF has antidepressant-like activity in learned helplessness paradigms and the forced swim test 19 Environmental stressors decrease central BDNF mRNA 8 Higher BDNF levels in the frontal cortex, occipital cortex, and hypothalamus of the 'depressed' FSL animals relative to the FRL controls 20 Decreased central BDNF in models of stress-induced depression 17,21,22 Downregulation of the Trk-B signaling pathway in the genetic animal models of depression 23 ECS, used as an ECT model, increases BDNF in the hippocampus, striatum, and occipital cortex 24 Lithium increases the expression of BDNF in the hippocampus and cortex of rats 25 BDNF in schizophrenia and depression F Angelucci et al tissue from schizophrenic subjects and MRI data in vivo suggest ongoing specific neurodegeneration. 43 There is also strong evidence suggesting that nonheritable factors in the pathogenesis of schizophrenia are associated with abnormalities during prenatal development.…”

“…This is further supported by an animal study demonstrating that environmental stressors, such as immobilization, decreased central BDNF mRNA. 8 Indeed, chronic stress downregulates neurotrophin synthesis causing atrophy and, in severe cases, death of vulnerable CA3 neurons in the hippocampus. 79 Stress also decreases the expression of BDNF in CA3 pyramidal and dentate gyrus granule cell layers of the hippocampus.…”

No association between the brain-derived neurotrophic factor gene and panic disorder in Japanese population

“…12 On the other hand, animal studies support the fact that environmental stressors, such as immobilization, decreased central BDNF mRNA. 13,14 BDNF-deficient mice show behavioral abnormalities, such as aggressiveness and hyperphagia, consistent with serotonergic dysfunction, which are corrected through antidepressant treatment. 15 A single-nucleotide polymorphism (SNP) of the BDNF, Val66Met (196C4T) or rs6265 in the coding region of exon XIII, has been reported to be associated with psychiatric disorders, such as Alzheimer's disease, 16 obsessive-compulsive disorder, 17 bipolar disorder 18 and eating disorders.…”