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 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.

Decreased Density of Perineuronal Net in Prelimbic Cortex Is Linked to Depressive-Like Behavior in Young-Aged Rats

“…TnR-deficient mice displayed abnormal postnatal development of PNNs and exhibited increased anxiety-like behavior and reduced exploration in the open field and elevated plus-maze tests (Brückner et al, 2000;Freitag et al, 2003). Genetic, pharmacological or environmental disruption of PNN assembly contributes to the pathogenesis of epilepsy, schizophrenia and other psychiatric disorders (Bitanihirwe et al, 2016;Testa et al, 2019).…”

Developmental disruption of perineuronal nets in the medial prefrontal cortex after maternal immune activation

“…However, it should be noted that alterations in some other measures such as ultrasonic vocalizations have been detected in polyI:C mouse offspring during the early postnatal period63. PNNs contribute to stabilizing neuronal structure, restricting neuronal plasticity, and supporting the physiological demands of host neurons646566. Disruption of this supportive matrix could destabilize neuronal connectivity and dysregulate their physiological activity, though this remains to be demonstrated experimentally.…”

Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

“…In schizophrenia, patients show reduced markers of GABA neuron function, particularly at PV interneurons in prefrontal cortex [43] and reduced density of PNNs [44-46], in addition to alterations in dendritic spines and markers of glutamatergic synapse function. Notably, PV interneurons in schizophrenia patients were recently found to receive fewer synaptic inputs from excitatory neurons than in control subjects, with excitatory input reductions predicting the downregulation of activity-dependent gene products in PV interneurons [47].…”

“…Notably, PV interneurons in schizophrenia patients were recently found to receive fewer synaptic inputs from excitatory neurons than in control subjects, with excitatory input reductions predicting the downregulation of activity-dependent gene products in PV interneurons [47]. Thus, although reduced PV interneuron function and PNN expression could directly contribute to cortical disinhibition and circuit level dysfunction in schizophrenia [46,48,49], changes in PV interneurons and PNNs might arise during development as compensatory responses to reduced pyramidal cell activity.…”