3.1. Pathophysiology of Schizophrenia

Schizophrenia is a complex psychiatric disorder, which likely arises from an elaborate, and as yet unknown, series of interactions between genetic and environmental factors. Schizophrenia clearly displays a "progressive" component, in which clinical manifestations, including cognitive deficits2, deteriorate with time, particularly during adolescence and early adulthood. Absence of neuro-degenerative pathology implicates neurodevelopmental factors in the etiology of psychotic disorders, and functional neuroimaging studies indicate abnormalities of connectivity, including altered patterns of correlation between regions for brain blood flow or metabolism3, in addition to abnormal cerebral activation following cognitive challenges4. Unlike the more advanced stages of neurodegenerative diseases, schizophrenia has been associated with relatively subtle, and often inconsistent, changes in brain architecture or pathology. This has led to the hypothesis that schizophrenia is primarily a disorder of "neural connectivity" or altered neurotransmission. Post mortem studies have indicated that molecules at the level of the synapse are likely substrates for altered connectivity and transmission .We have recently reviewed in detail the nature of synaptic deficits in schizophrenia5. Briefly, 16 of 19 studies of presynaptic proteins demonstrated differences in schizophrenia, as did eight of 12 studies of mRNA. Most reports indicated decreased synaptic proteins. More recent studies suggest the importance of networks of interacting presynaptic proteins; for example, using a cDNA screening strategy, reduced mRNAs for the synaptic protein synapsin II was observed consistently in schizophrenia6, while mRNAs coding for other presynaptic proteins were also affected, but less consistently. There is little information concerning functional implications of altered levels of presynaptic proteins. In cingulate and temporal cortex, increased synaptophysin immunoreactivity was correlated with increased severity of negative symptoms7, while studies of Alzheimer's disease noted that hippocampal reductions in synaptophysin and syntaxin were correlated with cognitive impairment8. Current evidence thus suggests that presynaptic proteins are necessary for normal cognitive function, but the identity of which proteins, in which brain regions, and on which cognitive indices, remains at present poorly understood.

3.2. Cognitive Deficits in Schizophrenia

Recent studies using powerful statistical techniques indicate that the sequelae of schizophrenia can be categorized into multiple separate factors, typically including a cluster characterized by deficits in cognition. This latter group of deficits, which are strongly associated with neuropsychological impairment, has recently been highlighted by major funding groups in the USA, including the National Institute of Mental Health, by programs such as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) cooperative initiative. Currently, efforts are underway to allow US government approval for the design of pharmacotherapies that treat specifically cognitive indications. Cognitive deficits reflect a diverse loss of function, so that it may be convenient to subcategorize them: it has been proposed that the three main types of cognitive deficit observed in schizophrenia occur in memory, attention and executive function9.

Recent adoption of standardized, operational procedures, such as the tasks performed in the Cambridge Neuropsychological Test Automated Battery (CANTAB), has provided accurate data about the precise types of cognitive deficits that occur in psychotic disorders. CANTAB has become a popular standardized test procedure due to its ability to decompose a set of complex tasks commonly used in clinical assessment into their cognitive elements10. Furthermore, many CANTAB tests are based on data extrapolated from animal studies, allowing for closely homologous behavioral tests to be used between humans and rodents; rigorous evaluation of the tasks has confirmed that cognition in both humans and rodents involves similar brain regional activations and sensitivities to pharmacological manipulations. Cognitive deficits in schizophrenia include memory dysfunction, with problems in both working and long-term memory11. Attentional deficits in schizophrenia include those at both a preconscious level, in tasks such as prepulse inhibition (PPI) to a startling stimulus12, as well as at a conscious level, in tasks such as sustained vigilance13. Tasks of executive function are performed especially poorly in schizophrenia, evident in tests such as the Wisconsin Card Sort Task and the "Tower of London" task in CANTAB14. Animal and human studies indicate that forebrain regions, including the frontal cortex, hippocampus, and basal ganglia, are particularly important for the performance of cognitive tasks of memory, attention, and executive function15,16.

As part of the ongoing research in our laboratory, we are committed to understanding in greater detail the relationship between synaptic changes in post mortem schizophrenia and premorbid cognitive impairment. By measuring levels of presynaptic proteins in brain regions that are essential for normal cognitive function, we have recently demonstrated significant associations between altered levels of three presynaptic proteins, complexins Cxs I and II, and SNAP-25, and cognitive impairment. Furthermore, rodents trained in different cognitive tasks display plasticity-associated regional changes in levels of presynaptic proteins. We now discuss in detail the relevance of each of these proteins to schizophrenia.

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