Abstract
Rapidly emerging evidence implicates perineuronal nets (PNNs) and extracellular matrix (ECM) molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer's disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the “quadripartite” synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction.
Highlights
The classic view of psychiatric disorders as “neuronal” disorders has been challenged in recent years by rapidly emerging evidence pointing to the involvement of the extracellular matrix (ECM), glial cells, and their interactions [1,2,3,4,5,6,7,8]
For the purpose of this review, we focus on the involvement of glutamatergic transmission and GABAergic inhibitory neurons in schizophrenia and discuss the potential contribution of ECM/perineuronal nets (PNNs) pathology to abnormalities affecting these systems
In schizophrenia, concurrent disruption of chondroitin sulfate proteoglycans (CSPGs) expression and molecular families interacting with PNN components may contribute synergistically to glutamatergic synapse dysregulation on neurons associated with PNNs
Summary
The classic view of psychiatric disorders as “neuronal” disorders has been challenged in recent years by rapidly emerging evidence pointing to the involvement of the extracellular matrix (ECM), glial cells, and their interactions [1,2,3,4,5,6,7,8]. This evidence represents a significant departure from mainstream views and is driving the field toward a growing understanding of these elements as closely interacting components of functional units, such as the “tetrapartite synapse.”. Neural Plasticity may be complex and far-reaching, spanning from disruption of axonal guidance, neuronal differentiation, and migration in early brain development to circuit consolidation and closure of critical periods in postnatal development and axonal signal conduction and regulation of the blood/brain barrier in the adult brain [1, 2, 31,32,33,34,35,36,37,38]
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