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.

Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30–100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann’s area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-β) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.

The pathophysiology of schizophrenia involves disturbances of information processing across brain regions, possibly reflecting, at least in part, a disruption in the underlying axonal connectivity. This disruption is thought to be a consequence of the pathology of myelin ensheathment, the integrity of which is tightly regulated by oligodendrocytes. In order to gain insight into the possible neurobiological mechanisms of myelin deficit, we determined the messenger RNA (mRNA) expression profile of laser captured cells that were immunoreactive for 2’, 3’-cyclic nucleotide 3’-phosphodiesterase (CNPase), a marker for oligodendrocyte progenitor cells (OPCs) in addition to differentiating and myelinating oligodendrocytes, in the white matter of the prefrontal cortex in schizophrenia subjects. Our findings pointed to the hypothesis that OPC differentiation might be impaired in schizophrenia. To address this hypothesis, we quantified cells that were immunoreactive for neural/glial antigen 2 (NG2), a selective marker for OPCs, and those that were immunoreactive for oligodendrocyte transcription factor 2 (OLIG2), an oligodendrocyte lineage marker that is expressed by OPCs and maturing oligodendrocytes. We found that the density of NG2-immunoreactive cells was unaltered, but the density of OLIG2-immunoreactive cells was significantly decreased in subjects with schizophrenia, consistent with the notion that OPC differentiation impairment may contribute to oligodendrocyte disturbances and thereby myelin deficits in schizophrenia.

Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann’s area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder.

Perineuronal nets (PNNs) are enigmatic structures composed of extracellular matrix molecules that encapsulate the soma, dendrites, and axon segments of neurons in a lattice-like fashion. Although the majority of PNNs condense around parvalbumin-expressing GABA(γ-aminobutyric acid)ergic interneurons, some glutamatergic pyramidal cells in the brain are also surrounded by PNNs. Experimental findings suggest pivotal roles of PNNs in the regulation of synaptic formation and function. There has also been an increasing body of evidence linking PNN abnormalities to schizophrenia. Interestingly, the number of PNNs progressively increases during postnatal development until plateauing around the period of late adolescence and early adulthood, which temporally coincides with the age of onset of schizophrenia. Given the established role of PNNs in modulating developmental plasticity, the PNN represents a possible candidate for altering the onset and progression of schizophrenia. Similarly, the reported function of PNNs in regulating the trafficking of glutamate receptors places them in a critical position to modulate synaptic pathology, considered a cardinal feature of schizophrenia. Here we discuss the physiological role of PNNs in neural function, synaptic assembly and plasticity in addition to how they interface with circuit/system mechanisms of cognition. An integrated understanding of these neurobiological processes should provide a better basis to elucidate how PNN abnormalities influence brain function and contribute to the pathogenesis of neurodevelopmental disorders such as schizophrenia.