Abnormal synaptic pruning in schizophrenia: Urban myth or reality?

One of the enduring puzzles about schizophrenia is the question of why it typically first occurs in late adolescence or early adulthood. Structural neuroimaging studies indicate that persons with schizophrenia show prominent progressive brain changes at this time. For example, Andreasen and colleagues recently reported on the largest longitudinal study to date looking at brain volume changes over time in a cohort of patients with schizophrenia who had a mean age at first episode of 25 years. They found decreases in multiple grey and white matter regions, and these changes were most pronounced early (2 yr) after intake for the first episode of psychosis. In addition, a meta-analysis of studies involving persons at high risk for schizophrenia reported baseline decreases in grey matter in frontal and temporal regions of those who later transition to psychosis. Almost invariably, any research paper discussing reasons for the age at onset of symptoms or the early grey matter changes during young adulthood in patients with schizophrenia will invoke abnormal synaptic pruning as a potential mechanism. But what do we actually know about synaptic pruning in patients with schizophrenia? Early electron microscopy (EM) studies by Huttenlocher and Dabholkar on postmortem brains from healthy humans showed that cortical synaptic density reaches a maximum at 2–4 years of age, when it is about double adult levels, with reduction in the number of synapses toward adult levels occurring mainly during adolescence. Synaptic pruning refers to this process of elimination of excess neuronal synapses. Consistent with early EM studies, in a recent study profiling the expression pattern of thousands of genes (the so-called “transcriptome”) in the prefrontal cortex across the human lifespan, Colantuoni and colleagues reported that expression of many genes involved in axonal and synaptic function peak during fetal life then decrease during infancy with continuing reductions through the first decade of life. Interestingly, using an extensive series of brains of intermediate ages, Petanjek and colleagues have recently provided evidence that synaptic elimination may be a more extended process continuing throughout the third decade of life before stabilization of synaptic density at adult levels. There is strong supporting evidence for the idea that developing synapses are selectively stabilized by neuronal activity, while excess synapses are subsequently eliminated. An abnormal increase in synaptic pruning generally implies that a normal complement of synapses is formed during development followed by an excess of elimination. But apparent “pruning” could also occur because of decreased development and stabilization of synapses. Neuropathologic studies in persons with schizophrenia indicate that there is no actual loss of neurons but that alterations in neuronal density, decreased neuronal size and/or decreases in the neuropil (axons+dendrites+glia) may account for the reductions in grey matter in persons with the disorder. In 1982, Feinberg speculated that schizophrenia might result “from a defect of synaptic elimination programmed to occur during adolescence.” Consistent with this hypothesis, at least 2 lines of evidence suggest that the brains of adult patients with schizophrenia have fewer synaptic connections in multiple brain regions (for a review, see Faludi and Mirnics). First, the majority of excitatory synaptic input in the brain involves asymmetric synapses onto dendritic spines, and postmortem brain studies have reported decreased spine density on cortical pyramidal cells from patients with schizophrenia compared with controls. It is mainly this type of axo-dendritic synapse onto spines that is eliminated during developmental synaptic pruning. Second, at a molecular level, numerous studies have demonstrated decreases in a variety of presynaptic protein markers in the brains of patients with schizophrenia. Whereas these studies are consistent with the conclusion that there are fewer synaptic connections in postmortem brains of patients with schizophrenia, it should be noted that these studies were performed on brains from adults and do not inform us about synaptic changes during the onset of symptoms in young adulthood. Neuroimaging studies of young patients with first-episode schizophrenia are able to target earlier developmental stages of the disorder, and some of these findings are consistent with enhanced synaptic pruning at this time. The pronounced loss of grey matter occurring in the early years after