Astrocytic Regulation of aberrant perineuronal net formation in Mecp2-null Neocortex

Rett syndrome (RTT), caused by mutations in MECP2, is a complex neurological disorder characterized by myriad physiological disruptions, including early closure of the critical period of developmental plasticity and precocious formation of perineuronal nets (PNNs). PNNs are lattice-like substructures of extracellular matrix (ECM) that enwrap specific subpopulations of neurons. PNNs are essential in the modulation of neuronal plasticity and brain maturation, and their enzymatic disruption can partially restore plasticity in adults and improve memory. Although precocious PNN formation is well-established in RTT, there is little known of the cellular, molecular, or biochemical underpinnings of their precocious formation. Further, whether precocious PNN formation is due to cell-autonomous or non-cell-autonomous mechanisms is not fully understood. While PNNs form on subsets of neurons throughout the brain, astrocytes secrete many ECM components that form PNNs, and they play a central role in controlling closure of the critical period. We have found increased expression of both neuron- and astrocyte-derived PNN components in the developing Mecp2-null cortex, and demonstrate that PNNs are structurally and biochemically mature at an earlier developmental stage. Further, Mecp2-null astrocyte conditioned media induces the expression of the key PNN component Hapln1 and causes enhanced PNN formation on wildtype neurons. This suggests that Mecp2-null astrocytes play a key role in the precocious formation of PNNs in RTT. These results provide essential insight into the mechanisms and structure of aberrant PNNs in Mecp2-null cortex, and identify potential new avenues for targeted rescue or reversal of the precocious closing of the critical period in RTT.