Weaving a Net of Neurobiological Mechanisms in Schizophrenia and Unraveling the Underlying Pathophysiology

Abstract 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 most PNNs condense around parvalbumin-expressing gamma-aminobutyric acidergic 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. Also, an increasing body of evidence links PNN abnormalities to schizophrenia. 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. We discuss the physiologic role of PNNs in neural function, synaptic assembly, and plasticity as well as 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.