Introduction

Schizophrenia and related forms of psychosis are among the most severe, persistent, and debilitating illnesses affecting young people. The worldwide prevalence of schizophrenia (narrowly defined, i.e., with a nuclear syndrome consisting mainly of first-rank systems at onset) is almost 1%, and occurs with a similar incidence across most cultures and geographical regions. The World Health Organization has reported that schizophrenia is the fourth leading cause of worldwide disability. In 1996, the financial costs of schizophrenia in Canada were estimated at $2.35 billion, and in the United States the estimated financial burden exceeded that for all forms of cancer1. The costs to the individual and their family in schizophrenia are also among the most exacting of those in all mental illnesses. Schizophrenia is typically characterized by a lengthy prodromal phase that may disrupt the teenage years, while full onset of florid symptoms occurs in early adulthood and persists for the lifetime, rendering the individual unable to function within society without therapeutic intervention. Incidence rates of suicide are also significantly greater than for the general population.

Considerable progress has been made in recent years in identifying molecular substrates that may contribute to the etiology and expression of schizophrenia. The post mortem brain tissue in schizophrenia is typically bereft of neuronal loss and there is absence of astrogliosis; nor is there any substantial evidence for apoptotic processes, providing strong evidence that schizophrenia is not a neurodegenerative disorder. Current theories thus emphasize the role of neurodevelopmental factors in the etiology of this disorder, and significant risk factors for schizophrenia include early life events, such as history of prenatal and birth complications, developmental abnormalities, urban place of birth, exposure to viruses and childhood social interaction. Evidence for markers of altered neurodevelopment in post mortem brain tissue has been widely reported, although most neuropathological signs are relatively modest. A greater burden of evidence suggests that the physiological basis for the disorder may be one of altered neural connectivities, in which the underlying pathophysiology of the condition is manifested at a synaptic level in the brain by abnormal "miswiring."

Dissection of the cellular and molecular basis of abnormalities of neural connectivity in schizophrenia has been particularly fruitful at the level of the synapse, where presynaptic proteins involved in the regulation of neurotransmitter release have shown consistent changes. These molecules, many of which are described in detail by other authors in this book, are essential for neural plasticity and presumably underlie much of the brain's capacity for basic cognitive processes, such as learning and memory. In the present chapter, we discuss the evidence that presynaptic proteins are altered in the brain in schizophrenia. This discussion also evaluates in detail recent data indicating that three specific presynaptic proteins, SNAP-25, Complexin I (Cx I), and Complexin II (Cx II), are not only altered in schizophrenia, but also may be specifically related to the types of cognitive impairment that are a characteristic symptom of this disorder.

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