Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses
Introduction
The maldevelopmental hypothesis of schizophrenic psychoses postulates that an altered cytoarchitectural structure of certain brain areas, dysconnections and changes in neural plasticity are the pathophysiological basis of this devastating group of diseases, and underlie the clinical symptomatology which is characterized by disturbed information processing and psychotic symptoms such as hallucinations, delusions and disorganized speech (Raedler et al., 1998, Scheibel and Kovelman, 1981, Weinberger and Lipska, 1995).
The inappropriate connectivity and altered biochemical functioning at the neuronal level are manifested clinically in the form of altered cognitive, emotional and intentional functioning (Bullmore et al., 1997, Weinberger, 1995, Weinberger and Lipska, 1995). This hypothesis is supported by a number of histopathological, morphological and clinical studies (Akbarian et al., 1993, Arnold et al., 1995, Arnold et al., 1991, Benes et al., 1991, Shenton et al., 1992, Weinberger and Lipska, 1995).
It is likely that these developmental deficits are relevant not only during prenatal embryo- and organogenesis, but persist throughout life, thus activating further structural changes during adolescent pruning of neurons and aging processes (DeLisi 1997).
On molecular and neurobiochemical levels, neurotrophic factors are likely to be involved in these developmental alterations. This group of molecules is responsible for prenatal neuronal differentiation and development, as well as for postnatal neural plasticity. Such considerations lead to the ‘neurotrophin hypothesis’ of schizophrenic psychoses (Thome et al., 1998). There are probably different pathomechanisms which can cause alterations of the neurotrophin system such as genetic, infectious and traumatic factors. Additionally, these factors may vary among different subtypes of schizophrenia. Changes at the level of the neurotransmitter system (dopamine, glutamate) can be interpreted as epiphenomena, since neurotrophic factors strongly interact with the neurotransmitter system and are even responsible for the neurotransmitter phenotype during embryo- and organogenesis.
The neurotrophins are a family of small (approx. 13 kDa), highly basic (pI 9–10.5) proteins which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT-4) and neurotrophin 5 (NT-5) (Barbacid, 1995, Barde, 1989, Lindsay et al., 1994). The neurotrophins bind with high affinity to receptors of the tyrosine kinase family (TrkA, B, C): NGF binds TrkA, BDNF and NT-4/5 bind TrkB, NT-3 binds TrkC and, to a lesser extent, TrkA (Barbacid, 1995, Dechant et al., 1994, Lindsay et al., 1994, Rodrı́guez-Tébar et al., 1992). In addition, there is a low-affinity neurotrophin receptor (p75 NTR) (Barbacid, 1995, Cheng and Mattson, 1994). The topographic distributions of individual neurotrophic factors (NTFs) and their receptors are quite distinct and are subject to considerable changes during the course of neural development (Altar et al., 1993).
NTFs are directly involved in cellular proliferation, migration, differentiation and the survival of neurons in the human central nervous system (Alderson et al., 1990, Barde, 1989, Hyman et al., 1991, Maisonpierre et al., 1990, Staecker et al., 1995, Widmer and Hefti, 1994). The NTFs are active not only during embryogenesis and organogenesis, they are also involved in nerve regeneration (Ip et al., 1993) and the maintenance of neural plasticity in adults (Knipper et al., 1994, Prakash et al., 1996), in that they regulate synaptic activity and neurotransmitter synthesis (Altar et al., 1997, Bartrup et al., 1997). A pathological alteration of the neurotrophic factor system may thus lead not only to neural maldevelopment, migrational deficits and dysconnections, proposed to be the characteristic pathogenetic features of the maldevelopmental hypothesis, but also to reduced neural plasticity, which would impair the individual's ability to adapt to crisis situations.
Therefore, alterations in the expression of these molecules could be responsible for morphological anomalies seen in the brains of schizophrenic patients. Thus, the neurotrophin hypothesis represents a possible neurobiochemical explanation for well-known maldevelopmental theories of schizophrenia which propose that disturbances in cell migration and neural development constitute the pathophysiological basis of schizophrenia.
The aim of the present study was to determine the concentrations of two members of the neurotrophin family (BDNF and NT-3) in different regions of post-mortem brain tissue of patients suffering from schizophrenic psychoses in comparison with the values of control subjects. This procedure allows a determination of whether there are alterations in the protein level of BDNF and NT-3 contents in schizophrenic patients and, if so, in which brain areas.
Section snippets
Subjects
First, 23 brains from non-psychotic individuals were examined, in order to determine the age-dependency of the neurotrophic factor levels. Then, for the comparison between controls and schizophrenia patients, the post-mortem brain tissue from 11 schizophrenic patients (8 females, 3 males) with a mean age (±S.E.M.) of 77.6±4.0 years (range 51–91) was carefully pairwise matched with that from 11 controls [7 females, 4 males; mean age (±S.E.M.): 77.2 ±2.5 years, range 62–90]. The brain areas
Influence of age, gender and post-mortem time on BDNF and NT-3 levels
BDNF and NT-3 concentrations in the control and patient groups were tested for dependence on post-mortem delay and age. There was no correlation with post-mortem time, indicating a high post-mortem stability of these neurotrophic factors. However, a statistically significant negative correlation with age was found (see Table 2) for BDNF concentration in frontal cortex (Fig. 1) and NT-3 concentration in hippocampus (Fig. 2). Neurotrophic factor levels in tissue were expressed as a function of
Discussion
The results of this study demonstrate that alterations in the level of neurotrophic factor expression can be detected in post-mortem brain originating from schizophrenic patients. These alterations exhibit a neuroanatomically differentiated pattern. Whereas BDNF levels were increased in the cerebral cortex and decreased in hippocampus of patients when compared with non-psychotic controls, NT-3 levels were reduced in the cortex of patients.
The alterations of the neurotrophic factor level in
Acknowledgements
This work was supported by an Alexander von Humboldt Research Fellowship and a grant of the German Research Council (DFG Th 698/1-1).
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