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

Abstract

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. parvalbumin interneuron | critical period | visual cortex | dark rearing | MeCP2

Maternal experience-dependent cortical plasticity in mice is circuit- and stimulus-specific and requires MECP2

“…Interestingly, we found that additional changes occur specifically to PV+ in the auditory cortex of heterozygous Mecp2 mutants (MeCP2 het ), namely increased expression of parvalbumin and intensification of perineuronal nets (PNNs). PNNs are glycoprotein structures in the extracellular matrix surrounding PV+ that act as physical barriers to or modulators of synaptic modifications, and actively control maturation of PV+ (Krishnan et al, 2015;Sorg et al, 2016;Miyata and Kitagawa, 2017;Sigal et al, 2019). Thus, PNNs are proposed to work in concert with elevated parvalbumin to act as 'brakes' on plasticity e.g.…”

Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis

“…The interneurons have complex dendritic arborization to regulate the activity of principal neurons. PNN has an indirect role over principal neurons via regulating synaptic plasticity (Sigal et al, 2019) and dendritic arborization (Stolp et al, 2019) of the interneuron. In addition, PNN plays a key role in retaining neuronal connectivity (Bikbaev et al, 2015).…”

Multiple particle tracking detects changes in brain extracellular matrix structure and predicts neurodevelopmental age

“…show that earlier in development, PNNs have greater structural heterogeneity (Sigal et al, 2019). This structural heterogeneity could necessitate larger data sets at the ages where PNNs are in the process of forming.…”