Background Perineuronal nets (PNNs) are extracellular matrix structures that enwrap many neurons in the brain. They regulate the postnatal experience-dependent maturation of brain circuits and maintain their functional integrity in the mature brain by stabilizing their synaptic architecture. Methods Eighty-six postmortem human brains were included in this study. We used Wisteria Floribunda agglutinin histochemistry to visualize PNNs to investigate whether the densities of PNNs in the prefrontal cortex (PFC) and primary visual cortex were altered in subjects with schizophrenia or bipolar disorder. In addition, we quantified the normal postnatal development of PNNs in the human PFC. Results Compared to the normal control subjects, the densities of PNNs were decreased by 70–76% in layers 3 and 5 of the PFC in schizophrenia but not in bipolar disorder. This finding was replicated in a separate group of schizophrenia and normal control subjects. In addition, PNN densities in the primary visual cortex were unaltered in either condition. Finally, the number of PNNs in the PFC increased during postnatal development through the peripubertal period until late adolescence and early adulthood. Conclusions These findings suggest that PNN deficit contributes to PFC dysfunction in schizophrenia. The fact that the timing of PNN development overlaps with the period when schizophrenia symptomatology gradually emerges raises the possibility that aberrant PNN formation may contribute to the onset of illness. Thus, characterization of the molecular mechanisms underlying PNN deficit may have important implications for the conceptualization of novel strategies for the diagnosis, treatment, early intervention and prevention of schizophrenia.

The expression of the gene that encodes clusterin, a glycoprotein that has been implicated in the regulation of many cellular processes, has previously been found in gene expression profiling studies to be among the most significantly differentially expressed genes in pyramidal and parvalbumin-containing inhibitory neurons in the cerebral cortex in subjects with schizophrenia. In this study, we investigated whether clusterin may also be dysregulated at the protein level in schizophrenia subjects. We found that, although the intracellular amount of clusterin may be unchanged, the level of extracellular, secreted clusterin appears to be significantly increased in schizophrenia subjects. It is speculated that this finding may represent a neuroprotective response to pathophysiological events that underlie schizophrenia.

No abstract