Synapse Pathology in Brain Structures Affected in Depression

This chapter is concerned with the question of whether adult mental illness is likely to arise from a loss of functioning synapses in the brain structures affected by maltreatment in childhood. We have shown in preclinical (animal) experiments that this loss of grey matter is likely due to the loss of synapses in these regions. If correct, it follows that the grey matter changes, reasonably easily detected in depressed patients with magnetic resonance imaging, are due to the loss of synapses. In the early 1970s we showed that synapse loss occurs over a couple of weeks during normal development of a mammal, with such loss subsequently shown to be true of humans. It was speculated that this loss was required for establishment of the mature wiring of the nervous system through a process called ‘synaptic pruning’. As the mechanism of synaptic pruning is likely to provide insights into synapse removal in mental illness, it is described here in some detail. Synaptic pruning is engineered by microglial cells in the brain, which are the resident macrophages of the innate immune system responsible for the removal by phagocytosis of pathogens. Significant levels of grey matter loss determined by magnetic resonance imaging are evident in the brains of adults who have suffered maltreatment as children, with areas that provide key functions in normal emotional expression, such as the medial and lateral prefrontal lobe especially targeted. It is suggested that it is the microglia in these areas which are promoted under stress to excess synapse pruning with subsequent grey-matter loss and the rise of MDD.