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PNNs are lattice\u2010like 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\u2010established in RTT, little is known of the cellular, molecular, or biochemical underpinnings of their precocious formation, or whether precocious PNN formation is due to cell\u2010autonomous or non\u2010cell\u2010autonomous mechanisms. 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 find that\n                    <jats:italic>Mecp2<\/jats:italic>\n                    \u2010null mouse astrocyte conditioned media induces the expression of the key PNN component\n                    <jats:italic>Hapln1<\/jats:italic>\n                    and causes enhanced PNN formation on wildtype mouse neurons in\u00a0vitro, suggesting that\n                    <jats:italic>Mecp2<\/jats:italic>\n                    \u2010null astrocytes play a key role in the precocious formation of PNNs in RTT. Further, we identify increased expression of HAPLN1 and other PNN\/ECM components in the developing mouse\n                    <jats:italic>Mecp2<\/jats:italic>\n                    \u2010null cortex, and demonstrate that PNNs are structurally and biochemically mature at an earlier developmental stage. These results provide essential insight into the mechanisms and structure of aberrant PNNs in\n                    <jats:italic>Mecp2<\/jats:italic>\n                    \u2010null cortex and identify potential new avenues for targeted rescue or reversal of the precocious closing of the critical period in RTT.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70503-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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