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.

Keywords: Critical period; Neurodevelopment; Parvalbumin interneurons; Perineuronal nets; Schizophrenia; Synaptic plasticity.

Figure 1

Schematic diagram of the potential neurobiological mechanisms associated with circuitry dysfunction in schizophrenia. During normal postnatal development, progressive increase in inhibitory inputs to pyramidal (PYR) neurons furnished by parvalbumin (PV) and somatostatin (SST) interneurons enables PYR neuronal circuits to oscillate in gamma and theta band frequencies, respectively. Epigenetic and genetic susceptibility in addition to microglia activation can provide a source of free radicals with the capacity to modify proteins, lipids, and nucleic acids (i.e., oxidative stress) that reduce N-Methyl-d-Aspartate (NMDA) receptor activity and which are potentially toxic for neurons and perineuronal nets (PNNs). The reduction in PNNs results in a deficit of OTX2 internalization into PV interneurons. As a consequence, PV-bearing PNNs are impaired, as manifested by alterations of local oscillations and distant synchronization. Because PNNs are protective of neurons from oxidative stress, PNN deficits may render them more vulnerable to oxidative injury. These cellular and molecular changes may alter the timing of critical periods.