Abstract
Background: Aberrant developmental synaptic elimination during adolescence has been suggested to contribute to both the reduced spine density of pyramidal cells (PCs) in the prefrontal cortex (PFC), and the cognitive deficits of schizophrenia. Recent data indicate that microglia (MG) are a major contributor to synaptic pruning during early postnatal periods. However, the role of MG in the structural and functional maturation of the PFC, which has a protracted postnatal development, has not been examined. We determined if MG contribute to the developmentally specific pruning of dendritic spines in the PFC of the rat, with a focus on synaptic modifications during adolescence.
Methods: Sprague-Dawley rats, weaned at 21 days of age, were used as subjects. Randomly selected L5 PCs from the prelimbic cortex of one hemisphere were intracellularly filled with Lucifer Yellow (LY) for dendritic spine density measurements. These LY fills were performed in rats sacrificed on postnatal (P) days 24 and 30 (a time of increasing PFC PC spine density), P35 (posited peak spine density), and P39 and P50 (decreasing spine density). The contralateral hemisphere was used to determine whether MG (identified by Iba1 expression) phagocytosed PFC PC dendritic spines (revealed by PSD-95-immunoreactivity).
Results: Dendritic spine density on PFC PCs peaked between P30 and P35. We observed a sharp increase in Iba1 and PSD-95 colocalization in the PFC at P39 relative to earlier ages, consistent with active MG pruning of dendritic spines on PFC PCs during adolescence. We also noted a nonsignificant trend (P = .06) toward MG engulfment of spines in male but not female rats at P39.
Conclusion: Our data suggest that the developmentally specific pruning of dendritic spines on PCs in the PFC occurs during adolescence, substantially later than in other areas of the brain. Ongoing studies are examining whether the presynaptic partners of spines are also engulfed by microglia during adolescence. These studies are a foundation for understanding the processes governing developmental PFC synaptic elimination. The adolescent surge in MG sculpting of PFC structure occurs at the time when premorbid behavioral changes (prodromal symptoms) first appear in youths who will subsequently have a psychotic break and is consistent with Feinberg’s hypothesis that abnormal enhancement of synaptic elimination is a key pathophysiological feature of schizophrenia. Our work may help guide the identification of pharmacological targets for early interventions designed to attenuate or prevent the cortical pathology and emergence of cognitive dysfunction in schizophrenia. We are currently determining if temporally specific ablation of microglia during adolescence leads to adult PFC PC pathology that mirrors that seen in schizophrenia.