Elucidating the pathogenesis of schizophreniaBMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7416.632 (Published 18 September 2003) Cite this as: BMJ 2003;327:632
- Akira Sawa, director (, )
- Atsushi Kamiya, postdoctoral fellow
- Cellular Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Meyer 2-181, Baltimore, MD 21287, USA
DISC-1 gene may predispose to neurodevelopmental changes underlying schizophrenia
Genetic predisposition to schizophrenia is evident from family, twin, and adoption studies.1–3 But whereas genetic factors contribute to the fundamental mechanisms or vulnerability to schizophrenia, additional influences including environmental factors are clearly involved in the full manifestation of symptoms of schizophrenia.4 Thus currently schizophrenia is best conceptualised as a “multiple hit” illness similar to cancer. This editorial looks at the fundamental mechanisms underlying the disease.
The following evidence implies that neurodevelopmental abnormalities contribute to susceptibility to schizophrenia.1 5 6 7 Firstly, clinical studies show that patients with schizophrenia manifest minor behavioural abnormalities in childhood even before the onset of schizophrenia.
Secondly, recent advanced imaging techniques such as magnetic resonance imaging provide reliable evidence of abnormalities during development of the central nervous system. Such abnormalities include consistent increases in ventricular size at the onset of schizophrenia, with notable alterations in some areas including the prefrontal cerebral cortex and hippocampus.
Thirdly, neuropathological studies indicate no overall loss in the number of neurones but reductions in the size of neurones. Cytoarchitectonic abnormalities include variability of cell orientation and decreased synaptic structures. In contrast to neurodegenerative diseases, in which proliferation of glial cells increases as neurones degenerate, no glial proliferation occurs in brains of patients with schizophrenia, implying that the primary disorder in schizophrenia is neurodevelopmental rather than neurodegenerative. Abnormalities in proteins that are key determinants of brain development and structure are often observed in autopsied brains from adult patients with schizophrenia. For example, changes are reported in microtubule associated protein 2 (MAP2), growth associated protein-43 (GAP-43), post-synaptic density protein 95 (PSD 95), and reelin. Reelin is a large secreted matrix protein that is involved in neuronal migration, facilitating normal brain architecture during development, and brains of patients with schizophrenia show a 30-50% reduction in reelin protein especially in the prefrontal cerebral cortex and hippocampus. Mutations in the reelin gene are also associated with a type of lissencephaly with cerebellar hypoplasia. Such a molecular association with cortical development disorder implies neurodevelopmental implications for schizophrenia.
Altogether it seems that genetic factors that have roles in cortical development are candidates for the underlying pathogenesis of schizophrenia. In this context, attention has recently been focused on a gene named disrupted in schizophrenia-1 (DISC-1). In a Scottish family, a chromosome (1;11)(q42.1; q14.3) translocation with disruption of DISC1 gene inside its open reading frame segregates with major psychiatric illnesses with a LOD (logarithm of odds) score of 7.1.8 This translocation interrupts the coding sequence of DISC-1, leading to loss of the C-terminal 257 amino acids of the DISC-1 protein. Linkage and association studies have also identified the DISC-1 locus as a susceptibility factor for schizophrenia in Finnish families and white people.9
Expression of DISC-1 displays pronounced developmental regulation, with concentrations highest in late embryonic life when the cerebral cortex develops. DISC-1 interacts with a variety of cytoskeletal proteins that are important in neurodevelopment.10 A cytoskeletal protein, NUDEL (NudE-like), which is one of the DISC-1 interactors, is associated with cortical development and linked to LIS-1 (the disease gene for a form of lissencephaly) as described above. The mutant form of DISC-1 in the Scottish family fails to bind NUDEL. Expression of mutant, but not wild type, DISC-1 in neuronal PC12 cells reduces neurite outgrowth. As schizophrenia is thought to reflect defects in cortical development determined by cytoskeletal proteins, the cellular disturbances with mutant DISC-1 may be relevant to psychopathological mechanisms. DISC-1 may be one of several susceptible factors for the pathogenesis of schizophrenia.
Nevertheless, there is precedence for focusing on causative factors of rare familial forms of diseases.11 Studies on Alzheimer's disease and Parkinson's disease in the past decade indicate how investigating the genes involved in rare familial forms of diseases can provide information on more general sporadic forms of neuropsychiatric conditions. The biology on amyloid precursor protein and presenilin has provided key mechanisms for the more common form of Alzheimer's disease. By analogy with this successful approach, focusing on rare forms of schizophrenia and the genes may also prove successful for more common forms of schizophrenia. Thus, DISC-1 is expected as a novel window towards the pathogenesis of schizophrenia.
Classic linkage analysis combined with analysis of schizophrenia associated single nucleotide polymorphisms within the linkage areas has clarified several other promising candidate genes, including neuregulin-1 and dysbindin.12 Interestingly, neuregulin-1 and dysbindin proteins are known to have important roles in neurodevelopment and synaptic functions, like DISC-1.
In addition to deficits in neural development, several aspects of the pathogenesis of schizophrenia have been studied, including dysfunctions of glutamatergic and dopaminergic neurotransmission. Possible environmental factors superimposed on genetic vulnerability include virus infection as well as gestational and birth complications. By studying genetically engineered mice with susceptibility factors such as DISC-1 in combination with environmental stresses, it may be possible to provide a more definitive, integrated model for the pathogenesis of schizophrenia in the future.
Competing interests None declared.