Schizophrenia as a Disorder of Developmentally Reduced Synaptic Connectivity

Abstract

Recent postmortem and neuroimaging studies of schizophrenia delineate changes in brain structure and volume that appear to arise from a reduction of neuritic processes (such as dendrites and synapses) rather than loss of neuronal or glial cell bodies. To account for these findings, we propose a pathophysiological model of reduced synaptic connectivity arising from disturbances of brain development active during perinatal and adolescent periods. We review a computer simulation of the elimination of the synaptic connections that models normal cognitive development and psychotic symptom formation. We describe the model's key parameters and discuss how they can account for important aspects of schizophrenia, including its unique symptoms, short- and long-term course, typical age of onset, neurodevelopmental deficits, limited neurodegenerative progression, sex differences, and more. We discuss some of the model's predictions and questions raised for basic research, early detection, and preventive intervention.

Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): A cross-sectional and longitudinal study

“…In neural networks models, hypoconnectivity or misconnectivity caused by excessive pruning has been suggested to decrease functional efficiency and to trigger abnormal perceptions comparable to hallucinations (Hoffman and McGlashan, 1997; Hoffman and McGlashan, 2006;McGlashan and Hoffman, 2000). However, the association between aberrant pruning and schizophrenic symptomatology remains difficult to prove in vivo, e.g.…”

S100B Serum Levels and Long-Term Improvement of Negative Symptoms in Patients with Schizophrenia

“…Since a healthy brain requires the potential to implement proliferative as well as differentiating mechanisms according to varying requirements, S100B should be present in balanced amounts (Donato, 2001;Rothermundt et al, 2003). We still do not know what causes the loss of dendrites and synapses in brains of schizophrenic patients (Harrison, 1999;Powers, 1999;Selemon and Goldman-Rakic, 1999;McGlashan and Hoffman, 2000), but from our knowledge concerning the mechanisms of regeneration and degeneration it appears likely that S100B might be involved in this process (Donato, 2001;Rothermundt et al, 2003). The increased S100B concentrations in patients with schizophrenia might cause a shift in the regeneration-degeneration balance towards degeneration so that a rarification of synapses and dendrites might result.…”

“…A classical neurodegenerative mechanism involving loss of neurons and development of gliosis, however, is unlikely to be relevant for schizophrenia. Brains from patients having suffered schizophrenia usually show unchanged numbers of neurons and a reduction in neuronal cell size and neuropil (Harrison, 1999;Powers, 1999;Selemon and Goldman-Rakic, 1999;McGlashan and Hoffman, 2000). A reduction of neuropil entails compromised cell structure and impoverishment of neuronal connectivity so that a loss in functional communication between neurons is presumed to occur.…”

Schizophrenia Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

“…Compared with normal controls, individuals with schizophrenia seem to undergo an exaggerated reduction of gray matter volume in the context of minimal neuronal loss (Selemon and Goldman-Rakic 1999;McGlashan and Hoffman 2000;Woods 1998). The gray matter volume deficits observed in schizophrenia appear to be already present at the onset of the disease and to be non-progressive (Gur et al 2000a,b; for review see Pearlson and Marsh 1999).…”

“…It is therefore possible that gray matter volume reductions represent genetically loaded deficits (Cannon et al 1998;Seidman et al 1999;Staal et al 2000;Gur et al 2000a,b;Baare et al 2001). These gray matter deficits could be due to an early underdevelopment of synaptic connectivity (which may result in smaller heads) or overaggressive pruning process occurring primarily in the pre-adolescence period which may result in normal head size but smaller brain volume at illness onset (McGlashan and Hoffman 2000;Woods 1998;Giedd et al 1999b;Rapoport et al 1999).…”