Microglial sculpting of prefrontal cortical synapses during development and the reduced neuropil hypothesis of schizophrenia

Abstract

Excessive synaptic elimination during adolescence has been suggested to reduce the density of dendritic spines on pyramidal cells (PCs) in the prefrontal cortex (PFC), thereby contributing to the cognitive deficits of schizophrenia. Recent data indicate that microglial phagocytosis is an important mechanism of synaptic pruning of neurons during early postnatal life. However, the role of microglia in the maturation of the PFC, which has a protracted postnatal development, has not been examined. I determined if microglia contribute to the synaptic sculpting of pyramidal cells in the rat PFC during adolescence. I found that microglia age-dependently phagocytose both pre- and postsynaptic elements of excitatory synapses on layer 5 (L5) PFC PCs. Shortly after peak spine density of L5 PCs, at postnatal day (P) 39, i.e., during early adolescence, microglia engulf dendritic spines. Microglia also phagocytose presynaptic elements during adolescence, at P39 and P50. Physiological removal of spines by microglia during development was not accompanied by classic morphological signs of microglial activation. My data point to a critical role for microglia in determining the adult architecture of PFC pyramidal cells. These findings also indicate that microglia prune excess spines on PFC neurons during adolescence, later than occurs in other brain regions. Microglia may also play a role in spine loss evoked by NMDA-R antagonist treatment in the adult. These studies form a foundation for understanding the processes governing the maturation of the PFC. Exaggerated pruning of synapses during adolescence has been posited to be a central pathophysiological feature of schizophrenia. The adolescent surge in microglial sculpting of PFC structure occurs at the time when premorbid behavioral changes first appear in individuals who subsequently suffer a psychotic break. Thus, microglia may be effectors of excessive synaptic pruning of PFC PCs during adolescence in schizophrenia. My findings may help guide the identification of novel microglial-based pharmacological targets for early interventions designed to attenuate or prevent the cortical pathology and emergence of cognitive dysfunction in schizophrenia.