Perineuronal nets and schizophrenia: the importance of neuronal coatings

Abstract

Schizophrenia is a complex brain disorder associated with deficits in synaptic connectivity. The insidious onset of this illness during late adolescence and early adulthood has been reported to be dependent on several key processes of brain development including synaptic refinement, myelination and the physiological maturation of inhibitory neural networks. Interestingly, these events coincide with the appearance of perineuronal nets (PNNs), reticular structures composed of components of the extracellular matrix that coat a variety of cells in the mammalian brain. Until recently, the functions of the PNN had remained enigmatic, but are now considered to be important in development of the central nervous system, neuronal protection and synaptic plasticity, all elements which have been associated with schizophrenia. Here, we review the emerging evidence linking PNNs to schizophrenia. Future studies aimed at further elucidating the functions of PNNs will provide new insights into the pathophysiology of schizophrenia leading to the identification of novel therapeutic targets with the potential to restore normal synaptic integrity in the brain of patients afflicted by this illness.

Keywords: Neurodevelopment; Neuronal protection; Parvalbumin; Perineuronal nets; Schizophrenia; Synaptic connectivity; Synaptic plasticity.

Figure 1

Chemical structure of Hyaulronan

Figure 2

Structures of the Lectican family of chondroitin sulfate proteoglycans

Figure 3

Domain structure of Tenascin-C and -R: Two key components of the perineuronal net

Figure 4

Schematic of perineuronal net organization through interactions with hyaluronan, link protein, tenascins and chondroitin sulfate proteoglycans

Figure 5. Postnatal development of perineuronal nets in the human prefrontal cortex

A. Photomicrographs demonstrating the increase in perineuronal nets (PNNs) in the prefrontal cortex during postnatal development. B. Linear regression analysis indicates statistically significant effect of age on PNN density in the entire prefrontal cortex (R²=0.45, p=0.0017) and in layer 3 (R²=0.49, p=0.0008), suggesting that the density of PNNs in the prefrontal cortex undergoes a prolonged course of progressive increase during postnatal development through adolescence and early adulthood. However, the nonlinear hyperbolic regression models appear to be a better fit of the data (R²=0.71 and 0.76 for the entire prefrontal cortex and layer 3, respectively); these models suggest that PNN density increases during postnatal development with the most pronounced changes occurring around the peri-pubertal period. These findings were derived from postmortem human brains from 19 healthy control subjects obtained from the National Institute of Child and Human Development Brain and Tissue Bank at the University of Maryland in Baltimore, MD. Reproduced with permission of Springer-Verlag, Heidelberg.

Figure 6. Densities of perineuronal nets in the prefrontal cortex in subjects with schizophrenia

A. Representative photomicrographs showing the distribution of perineuronal nets (PNNs) in the prefrontal cortex in a schizophrenia (right) and a normal control (left) subjects. Scale bar=100μm. B. Photomicrograph showing a WFA-labeled PNN. Scale bar=20μm. C. WFA-labeled PNNs are significantly decreased in layers 3 (70%) and 5 (76%) in subjects with schizophrenia (SZ; N=16). Bar graphs represent the mean and upper 95% confidence interval by cortical layer. Layer 1 is not shown because no PNNs were found in that layer. There are no significant differences in PNN densities between subjects with bipolar disorder (N=15) and normal control (N=16) subjects. p value, F ratio: *(0.016, 6.49); **(0.028, 5.36); ***(0.042, 4.51). These findings were derived from postmortem human brains obtained from the Harvard Brain Tissue Resource Center in Belmont, MA. Reproduced with permission of Springer-Verlag, Heidelberg.