Crusio, Wim E. (1991) The neuropsychology of schizophrenia: A
perspective from neurobehavioral genetics. Behavioral and Brain
Sciences 14 (1) 23-24.
Commentary on Gray, J. A., Feldon, J., Rawlins, J. N. P., Hemsley D. R. & Smith, A. D. (1991) The neuropsychology of schizophrenia, BBS, 14 (1) 1
Wim E. CrusioGénétique, Neurogénétique et Comportement,
Electronic mail: UGNC002@FRORS31.bitnet
Gray et al. have presented an admirable integration of an enormous amount of both clinical and experimental data (deriving from many different fields: neurology, psychiatry, neuroanatomy, neurochemistry, etc.) to arrive at the most complete hypothesis about the neural bases of schizophrenia to date. According to their model, most disruptions of the complex neural pathways involved will lead to schizophrenic symptoms. Both genetic and environmental influences may, separately or together, have multiple effects at many different places in these neural systems. Hence, one of the strengths of the present model is that it provides a way to explain schizophrenia's well-known heterogeneity with regard to symptomatology (e.g., Dworkin et al. 1988; Van Eerdewegh et al. 1987) and presence or absence of certain biological markers in defined subgroups of patients (e.g., Markianos et al. 1990), but also with regard to the genetic correlates underlying this psychiatric disease (e.g., Baron 1986; Faraone and Tsuang 1985; Kennedy et al. 1988).
I disagree with the authors, however, where they state, in the final paragraph of the target article, their belief that it would be futile, at least at this stage, to speculate about which of the many possible interruptions in the neural circuits they have described is primary. Of course, because schizophrenia seems to be more like a heterogeneous set of disorders than a well-defined syndrome, there just might not exist a single primary interruption. Others, however, have argued in favor of a unitary concept of schizophrenia (e.g., Heath et al. 1989). If that were true, then there might indeed exist only one single primary interruption. Damage to the hippocampal system is a good candidate for this primary lesion that leads ultimately to schizophrenia. This hypothesis is supported by several findings, of which I mention two.
First, it has been observed that pregnancy or birth complications (PBCs) increase a person's risk of developing schizophrenia (Mednick 1974). These PBCs include anoxia, prolonged labor, multiple births, and so on. Cerebral ischemia is known to lead to the release of glutamate in the hippocampus, which has an excitotoxic action that may be reinforced by the simultaneous release of zinc (Tonder et al. 1990), resulting in neuronal cell loss in the hippocampus. Second, serum obtained from schizophrenic patients has recently been shown to contain an antibody, a subfraction of gamma G immunoglobulin, which is reactive against an antigen occurring primarily in the septal region of the brain (Heath et al. 1989).
These findings suggest a number of possible causes for schizophrenia (PBCs; immunological disorder, possibly induced by viral action), but all acting via the same or almost the same primary lesion to the septohippocampal system. Similar considerations have led Schmajuk (1987) to propose that hippocampally lesioned animals might constitute an animal model of schizophrenia. Since hereditary factors might predispose certain individuals to susceptibility to environmentally induced neural damage, I suggest that an even more appropriate model may be found when different inbred strains are compared for their susceptibility to anoxia. Also, not all schizophrenic patients have experienced PBCs and schizophrenia shows familial aggregation (see Gottesmann & Shields 1982), suggesting that purely hereditary factors may sometimes be the sole cause of schizophrenia. Large heritable differences in hippocampal anatomy can be found between different inbred mouse strains (Crusio et al. 1986), particularly with regard to the sizes of their infra- and intrapyramidal mossy fiber (IIP-MF) terminal fields. Note that the hippocampal mossy fibers, being the axons of dentate granule cells that form synapses on the dendrites of hippocampal pyramidal cells in area CA3, constitute a bottle-neck in the flow of information into the hippocampus (cf. Fig. 4, where the mossy fiber projection is indicated by the word "Gate"). It might therefore be worthwhile to investigate the possibility that certain inbred strains provide a genetic model of schizophrenia. From experiments carried out in our laboratory, it would appear that strains such as DBA/2, NZB/B1N, or CPB-K are likely candidates. These have only small projections of the zinc-containing IIP-MF (Crusio et al. 1987) and exhibit a number of features that are characteristic for hippocampally lesioned animals such as poor learning in spatial radial-maze tasks (Crusio et al. 1987; Schwegler et al. 1990) combined with good performance in two-way active-avoidance tasks (Lipp & Schwegler 1983). We may speculate that these mice suffer a hereditary malfunction of their septohippocampal system, a notion supported by psychopharmacogenetic evidence (van Abeelen 1989). An interesting question is whether these mice also exhibit other neurological features that are found in schizophrenic patients.
The foregoing speculation about the possibility that the primary origin of schizophrenia is damage to the septohippocampal system need not contradicth the observed heterogeneity of the schizophrenic syndrome. It might well be that in combination with the initial septohippocampal damage, whatever its origin, multiple genetic and environmental effects exert modulating influences on some of the different components of the neural circuits described by Gray et al. and thereby cause the heterogeneous appearance of the schizophrenic syndrome. I suggest that multivariate genetic studies, simultaneously investigating psychiatric and neurological variables (selected according to Gray et al.'s model) combined with studies along the lines proposed by Vogel and Motulsky (1986, p. 607), will provide some clues to unravel the complex etiology of schizophrenia.
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