Elsevier

Schizophrenia Research

Volume 81, Issue 1, 1 January 2006, Pages 47-63
Schizophrenia Research

Apoptotic mechanisms and the synaptic pathology of schizophrenia

https://doi.org/10.1016/j.schres.2005.08.014Get rights and content

Abstract

The cortical neuropathology of schizophrenia includes neuronal atrophy, decreased neuropil, and alterations in neuronal density. Taken together with evidence of decreased synaptic markers and dendritic spines, the data suggest that synaptic circuitry is altered. Recent neuroimaging studies also indicate that a progressive loss of cortical gray matter occurs early in the course of schizophrenia. Although the mechanisms underlying these deficits are largely unknown, recent postmortem data implicate a role for altered neuronal apoptosis. Apoptosis, a form of programmed cell death, is regulated by a complex cascade of pro- and anti-apoptotic proteins. Apoptotic activation can lead to rapid neuronal death. However, emerging data also indicate that sub-lethal apoptotic activity can lead to a limited form of apoptosis in terminal neurites and individual synapses to cause synaptic elimination without cell death. For example, in Alzheimer's disease, a localized apoptotic mechanism is thought to contribute to early neurite and synapse loss leading to the initial cognitive decline. Recent studies indicate that apoptotic regulatory proteins and DNA fragmentation patterns are altered in several cortical regions in schizophrenia. This paper will review converging lines of data that implicate synaptic deficits in the pathophysiology of schizophrenia and propose an underlying role for apoptotic dysregulation.

Introduction

Schizophrenia is a chronic and often debilitating illness which affects about 1% of the world population. In addition to severely disrupting the life of the patient and their family, schizophrenia incurs a great cost to society in terms of lost productivity and treatment-related expenses. Although the etiology remains unknown, converging lines of evidence, including reduced gray matter volume, reduced synaptic markers and reduced neuropil, suggest that disrupted cortical synaptic circuitry is a central deficit in schizophrenia (Lewis and Lieberman, 2000). The underlying mechanisms that lead to synaptic dysfunction are also uncertain; however, evidence suggests that a dysregulation of neuronal apoptosis, a form of programmed cell death, may contribute to the pathophysiology of schizophrenia (Benes et al., 2003, Jarskog et al., 2004). Altered regulation of the apoptotic cascade can potentially reduce neuronal and glial viability at various stages of neural development and contribute to the volumetric and functional brain deficits observed in schizophrenia. In particular, apoptosis has been identified as a potential underlying mechanism for evidence of progressive gray matter volume loss seen around the first onset of psychosis (Berger et al., 2003, Jarskog et al., 2005). Given that apoptotic mechanisms are increasingly recognized for involvement in localized synaptic and neuritic loss, this paper will consider the hypothesis that apoptotic mechanisms contribute to the synaptic deficits of schizophrenia.

Section snippets

Neuropil and synaptic markers

Neuropil comprises axons, dendrites, and the pre- and postsynaptic terminals between them. The “reduced neuropil hypothesis” suggests that reduced cortical neuropil rather than an absolute change in neuron number represents a core pathophysiological feature of schizophrenia (Selemon and Goldman-Rakic, 1999). Evidence includes increased neuronal density of 13–21% (layers III–VI) and 10–15% in frontal and occipital cortices, respectively, of subjects with schizophrenia, (Selemon et al., 1995,

Structural and functional neuroimaging

Neuroimaging has contributed to our understanding of the pathophysiology of schizophrenia by demonstrating limited cortical gray matter loss, consistent with postmortem studies that have found reduced neuropil. Furthermore, the advent of functional neuroimaging has provided in vivo data on the underlying neurochemical pathophysiology of schizophrenia. This section will review structural and functional neuroimaging studies in schizophrenia with a focus on cortical neuropil and synapses.

Apoptosis

Apoptosis is a highly regulated form of cell death that is often likened to cellular suicide. Apoptosis is morphologically and molecularly distinct from necrosis, the other principal form of cell death (Sastry and Rao, 2000). Cytomorphological features of apoptosis include cell shrinkage, membrane blebbing, chromatin condensation, DNA fragmentation, and cellular disintegration via phagocytosis (Wyllie et al., 1980). Apoptosis occurs without inflammation and generally requires the formation of

Conclusion

The study of apoptotic regulation in schizophrenia has demonstrated abnormalities in both upstream and downstream components of the apoptotic cascade that may increase the vulnerability to apoptotic activity in neurons and glia. Although the consequences of apoptotic dysregulation in schizophrenia remain uncertain, the fact that apoptotic mechanisms can influence synaptic connectivity and neuritic complexity provides support for an apoptotic hypothesis of schizophrenia. It is proposed that

Acknowledgements

Work supported by NARSAD Young Investigator Award (LAG), NIMH grants MH-01752 (LFJ), MH-60352 (JHG), MH-64065 (JAL).

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