Postmortem evidence of microglial involvement in the child abuse-associated increase of perineuronal nets in the ventromedial prefrontal cortex

Abstract

Microglia, versatile in their functions within the central nervous system, have recently been recognized for their capacity to degrade extracellular matrix. Perineuronal nets (PNNs), a specialized form of this matrix, are crucial for stabilizing neuronal connections and constraining plasticity. Our group recently reported increased PNN densities in the ventromedial prefrontal cortex (vmPFC) of adult depressed suicides with a history of child abuse, compared to matched controls. To explore the underlying mechanisms, we used here a comprehensive approach in similar postmortem vmPFC samples, combining a human matrix metalloproteinase array, isolation of CD11b-positive microglia and enzyme-linked immunosorbent assays. Our results indicate a significant downregulation of matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-2 in both whole vmPFC grey matter and isolated microglia. Furthermore, our experiments revealed that a history of child abuse was associated with a dampening of intercellular communication between microglia and neurons through CX3CR1 and IL33R. Taken together, these findings suggest that microglial function is lastingly disrupted in the vmPFC of adults having experienced sever adversity during childhood, thus providing a potential mechanism for the previously reported child abuse-associated PNN alterations.