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Abnormal Expression of Brain-Derived Neurotrophic Factor and Its Receptor in the Corticolimbic System of Schizophrenic Patients

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Abnormal Expression of Brain-Derived Neurotrophic Factor and Its Receptor in the Corticolimbic System of Schizophrenic Patients Molecular Psychiatry (2000) 5, 293–300 2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients M Takahashi1,2, O Shirakawa3, K Toyooka1, N Kitamura3, T Hashimoto3, K Maeda3, S Koizumi4, K Wakabayashi5, H Takahashi5, T Someya2 and H Nawa1 1Molecular Neurobiology, Brain Research Institute, Niigata University, 951–8585, Japan; 2Department of Psychiatry, Niigata University School of Medicine, 951–8510, Japan; 3Department of Psychiatry and Neurology, Kobe University School of Medicine, 650–0017, Japan; 4Novartis Pharma, Takarazuka, Hyogo Pref, 665–8666, Japan; 5Pathology & Brain Disease Research Center, Brain Research Institute, Niigata University, 951–8585, Japan Previous neuropathological studies have revealed that the corticolimbic system of schizo- phrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we deter- mined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influ- enced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. How- ever, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither with- drawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness. Molecular Psychiatry (2000) 5, 293–300. Keywords: neurotrophin; BDNF; TrkB; calbindin-D; development; haloperidol; postmortem brain Introduction to the aberrant synaptic transmission of the mature brain, both of which seem to be comprised in the brain Abnormal structural and neurochemical development, dysfunction of schizophrenics. To assess potential con- resulting in abnormal neural circuitry and function, tribution of BDNF to such pathological phenotypes of has been implicated in schizophrenia.1,2 Recently, a schizophrenic patients, we quantitated levels of BDNF, family of neurotrophic factors, comprising nerve together with other neurotrophins, NGF and NT-3, growth factor (NGF), BDNF, neurotrophin-3 (NT-3) and using two-site enzyme immunoassay (EIA)16,17 and neurotrophin-4/5, have been suggested to be potent attempted to correlate these findings with the regulators of neuronal phenotypic differentiation and expressions of BDNF receptors (TrkB) and calbindin D, synaptic plasticity in mammals.3–6 In addition, there is which may reflect the activity of BDNF in patients.18,20 growing evidence that these neurotrophins are involved in the cerebral structural organization such as the formation of the ocular dominance column, the Materials and methods whisker representation pads and neocortical layers.7–9 Human tissue sampling Together with the findings that BDNF regulates pheno- Brain tissue was collected posthumously from 18 typic expressions of brain neurons,10–15 these obser- patients with chronic schizophrenia (10 men, eight vations imply that abnormal signals of neurotrophins women; mean age: 61.6 years; SD: 15.2) and from 36 could lead to the malformation of cortical circuitry or controls (23 men, 13 women, mean age: 59.4 years; SD: 12.9) who had no history of neuropsychiatric disorders (Table 1). All the schizophrenics had taken typical Correspondence: H Nawa, Department of Molecular Biology, antipsychotics for prolonged periods, but six of them Brain Research Institute, Niigata University, Asahimachi-dori 1– had been off medication for at least 3 months before 757, Niigata 951–8585, Japan. Present address of N Kitamura, Kobe City Central Hospital, death. The diagnoses of schizophrenia corresponded to Kobe, Japan. the DSM-IV categories (American Psychiatric Associ- Received 6 October 1999; revised and accepted 6 December 1999 ation, 1994). The prefrontal cortex was sampled from Neurotrophins and schizophrenia M Takahashi et al 294 Table 1 Autopsy and clinical data Sex/age Cause of death Subtype Duration (year) Medication PMI PFC ACC HIP OCC (years) (DSM- dose − IV)illness medication (mg day 1) Schizophrenia S-1 M/23 Suffocation 295.1 1 1 Lev (40), 23 * * * Tri (30) S-2 F/40 Drowning 295.1 19 16 Hal (2.25), 24 * * Chl (12.5) S-3 F/44 Heart failure 295.1 15 15 Thr (30) 17 * * S-4 M/49 Heart failure 295.3 26 11 Hal (4.5) 5 * S-5 M/53 Heart failure 295.1 36 18 Off-drug 5 **** S-6 M/58 Gastric cancer 295.9 31 4 Hal (3) 19 * S-7 M/61 Heart failure 295.1 38 27 Chl (40) 9 * * S-8 F/63 Heart failure 295.9 10 10 Off-drug 4 * * * S-9 F/63 Gastric cancer 295.1 35 23 Hal (4) 6 * S-10 F/65 Panperitonitis 295.3 16 9 Tht (60) 15 **** S-11 M/66 Gastric cancer 295.1 45 35 Off-drug 9 **** S-12 M/70 Heart failure 295.3 35 26 Thr (75), 22 **** Oxy (60) S-13 F/72 Pneumonia 295.3 34 21 Chl (100) 3 **** S-14 F/72 Pneumonia 295.9 37 21 Off-drug 18 * * * S-15 F/73 Myocardial infarction 295.3 27 27 Off-drug 16 **** S-16 M/74 Unknown 295.3 21 21 Hal (2.25), 7 * Lev (100) S-17 M/80 Heart failure 295.1 29 25 Pro (30) 36 * * * S-18 M/83 Decrepitude 295.1 54 15 Off-drug 5 * * * Control C-1 M/35 Bleeding WND None 17 * * C-2 M/42 Bleeding WND None 4 * * C-3 F/42 Fresh muscle necrosis WND None 6.5 * * C-4 F/44 Gorham’s disease WND None 6 **** C-5 M/45 Cardiac hypertrophy WND None 11.5 * C-6 M/45 Cerebral infarct WND None 2 * * C-7 M/47 Myositis WND None 2 * * C-8 F/47 Bleeding WND None 10 * * C-9 F/48 Myasthenia gravis WND None 3 * * * C-10 M/49 Falling WND None 2 * * * C-11 F/49 Myopathy WND None 3 **** C-15 F/50 Castleman’s disease WND None 3 * C-13 M/51 Pontine hemorrhage WND None 5 * * C-14 M/55 Suffocation WND None 6 * * C-15 F/57 Heart failure WND None 2 * * C-16 M/59 Pulmonary tuberculosis WND None 9 * C-17 M/59 Myeloma WND None 2 **** C-18 M/59 Cerebral hemorrhage WND None 4 * * C-19 F/59 Myopathy WND None 3 * * * C-20 M/61 Amyloid neuropathy WND None 7 * C-21 M/61 Lung cancer WND None 2 * C-22 M/62 Bleeding WND None 2 * C-23 M/65 Pulmonary infarction WND None 6 * * * C-24 F/65 Heart failure WND None 4 * * * C-25 M/68 Cerebral infarct WND None 3 **** C-26 F/69 Heart failure WND None 22 * * C-27 M/70 Heart failure WND None 3 * * C-28 M/70 Gastric cancer WND None 5 * C-29 M/72 Myasthenia gravis WND None 3 * * * C-30 M/73 Cerebral infarct WND None 3 * * C-31 F/73 Neuropathy WND None 4 **** C-32 F/76 Retroperitoneal malignant WND None 5 **** tumor Continued Molecular Psychiatry Neurotrophins and schizophrenia M Takahashi et al 295 Table 1 Continued Sex/age Cause of death Subtype Duration (year) Medication PMI PFC ACC HIP OCC (years) (DSM- dose − IV)illness medication (mg day 1) C-33 M/77 Gastric cancer WND None 6 * * * C-34 M/81 Cardiac tamponade WND None 6 * C-35 F/82 Renal failure WND None 10 * * C-36 M/84 Decrepitude WND None 13 * * * M, male; F, female. 295–1, disorganized type; 295–3, paranoid type; 295–9, undifferentiated type; WND, without neuropsychiatric disease. Lev, levomepromazine; Tri, trimipramine; Hal, haloperidol; Chl, chlorpromazine; Thr, thioridazine; Tht, thiotixene; Oxy, oxy- pertine; Pro, propericiazine; Off-drug, no neuroleptic treatment for at least 3 months before death. PMI, postmortem interval (h). PFC, prefrontal cortex; ACC, anterior cingulate cortex; HIP, hippocampus; OCC, occipital cortex. Asterisk indicates available subjects in each region. the dorsolateral prefrontal cortex (BA46) and the Enzyme immunoassay anterior cingulate from the area BA24. The hippocam- Neurotrophin levels were measured by two-site pal tissue taken did not include the surrounding enzyme immunoassay (EIA) as described pre- entorhinal and parahippocampal areas. All the anatom- viously.16,17 In brief, tissue extracts (10–100 ␮l; ical orientation was based on the Human Brain Atlas.19 duplicate) or neurotrophin standards (1–300 pg; The families of the control and schizophrenic subjects triplicate) were loaded into the wells of EIA titer plates provided written informed consent for the use of brain that had been coated with 100 ng well−1 anti-BDNF, tissues as materials for the investigations. For determi- anti-NGF or anti-NT-3 antibody (primary antibody). nation of neurotrophin concentrations, tissues were Biotinylated anti-BDNF, anti-NGF or anti-NT-3 anti- homogenized in 20–50 vol homogenization buffer body (secondary antibody; 10–30 ng ml−1) was added [50 mM Tris, 0.3 M NaCl, 0.3% Triton X-100, 1% bov- to the wells, and then bound biotinylated secondary ine serum albumin (BSA; Corn Fraction V), pH 7.5] antibodies were detected using streptavidin-␤-galacto- containing protease inhibitors [aprotinin (200 kalli- sidase (1:10 000; Sigma). The activity of ␤-galactosidase krein units ml−1), 0.1 mM phenylmethanesulfonyl flu- retained in each well was measured by incubation with oride, 0.1 mM benzethonium chloride and 1 mM 200 mM 4-methylumbelliferyl-␤-d-galactosidase benzamidine (Sigma, St Louis, MO, USA)].20 Homogen- (MUG, Sigma).
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