Structural maturation of cortical perineuronal nets and their perforating synapses revealed by superresolution imaging

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (14), p.7071-7076
• Main Authors: Sigal, Yaron M., Bae, Haneui, Bogart, Luke J., Hensch, Takao K., Zhuang, Xiaowei
• Format: Article
• Language: English
• Subjects: Acceleration; Animals; Biological Sciences; Brain; Clonal deletion; Cortex (somatosensory); Critical period; Developmental plasticity; Gene deletion; Glutamic acid transporter; Imaging; Interneurons; Light diffraction; Light microscopy; Male; Maturation; MeCP2 protein; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Nerve Net - diagnostic imaging; Nerve Net - metabolism; Neuroimaging; Neuronal Plasticity; Neurons; Parvalbumin; Perforating; Perineuronal nets; Photovoltaic cells; Physical Sciences; Plastic properties; Plasticity; Regression analysis; Rett syndrome; Rett Syndrome - diagnostic imaging; Rett Syndrome - genetics; Rett Syndrome - metabolism; Sensory deprivation; Solar cells; Synapses; Synapses - genetics; Synapses - metabolism; Synaptotagmin; Synaptotagmin II; Synaptotagmin II - genetics; Synaptotagmin II - metabolism; Thalamus; Trajectories; Visual cortex; Visual Cortex - diagnostic imaging; Visual Cortex - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1817222116

Parvalbumin-positive (PV+) interneurons play a pivotal role in orchestrating windows of experience-dependent brain plasticity during development. Critical period closure is marked by the condensation of a perineuronal net (PNN) tightly enwrapping subsets of PV+ neurons, both acting as a molecular brake on plasticity and maintaining mature PV+ cell signaling. As much of the molecular organization of PNNs exists at length scales near or below the diffraction limit of light microscopy, we developed a superresolution imaging and analysis platform to visualize the structural organization of PNNs and the synaptic inputs perforating them in primary visual cortex. We identified a structural trajectory of PNN maturation featuring a range of net structures, which was accompanied by an increase in Synaptotagmin-2 (Syt2) signals on PV+ cells suggestive of increased inhibitory input between PV+ neurons. The same structural trajectory was followed by PNNs both during normal development and under conditions of critical period delay by total sensory deprivation or critical period acceleration by deletion of MeCP2, the causative gene for Rett syndrome, despite shifted maturation levels under these perturbations. Notably, superresolution imaging further revealed a decrease in Syt2 signals alongside an increase in vesicular glutamate transporter-2 signals on PV+ cells in MeCP2-deficient animals, suggesting weaker recurrent inhibitory input between PV+ neurons and stronger thalamocortical excitatory inputs onto PV+ cells. These results imply a latent imbalanced circuit signature that might promote cortical silencing in Rett syndrome before the functional regression of vision.