title: Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia.
abstract: Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons.
authors.affiliation: Translational Neuroscience Laboratory, Mclean Hospital, 115 Mill St., Belmont, MA 02478, USA; Dept. of Psychiatry, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA. Electronic address: s.berretta@mclean.harvard.edu.
authors.forename: Sabina
authors.initials: S
authors.lastname: Berretta
authors.affiliation: Translational Neuroscience Laboratory, Mclean Hospital, 115 Mill St., Belmont, MA 02478, USA; Dept. of Psychiatry, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Pantazopoulos
authors.affiliation: Translational Neuroscience Laboratory, Mclean Hospital, 115 Mill St., Belmont, MA 02478, USA; Dept. of Psychiatry, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
authors.forename: Matej
authors.initials: M
authors.lastname: Markota
authors.affiliation: Translational Neuroscience Laboratory, Mclean Hospital, 115 Mill St., Belmont, MA 02478, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brown
authors.affiliation: Translational Neuroscience Laboratory, Mclean Hospital, 115 Mill St., Belmont, MA 02478, USA; Dept. of Psychiatry, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA.
authors.forename: Eleni T
authors.initials: ET
authors.lastname: Batzianouli
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D005109:Extracellular Matrix / Q000473:pathology; D006801:Humans; D007395:Interneurons / Q000473:pathology* / Q000502:physiology*; D012559:Schizophrenia / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid
keywords: Amygdala; Entorhinal cortex; Extracellular matrix; Perineuronal nets; Prefrontal cortex; Schizophrenia