Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia

Abstract

Alterations in cortical parvalbumin (PV)-containing neurons, including a reduced density of detectable neurons and lower PV levels, have frequently been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects. Most PV neurons are surrounded by perineuronal nets (PNNs) and the density of PNNs, as detected by Wisteria floribunda agglutinin (WFA) labeling, has been reported to be lower in schizophrenia. However, the nature of these PNN alterations, and their relationship to disease-related changes in PV neurons, has not been assessed. Using confocal microscopy, we quantified the densities and fluorescence intensities of PV neurons and PNNs labeled with WFA or immunoreactive for the major PNN protein, aggrecan, in the DLPFC from schizophrenia and matched comparison subjects. In schizophrenia, the densities of PV cells and of PNNs were not altered; however, the fluorescence intensities of PV immunoreactivity in cell bodies and of WFA labeling and aggrecan immunoreactivity in individual PNNs around PV cells were lower. These findings indicate that the normal complements of PV cells and PNNs are preserved in schizophrenia, but the levels of PV protein and of individual PNN components, especially the carbohydrate moieties on proteoglycans to which WFA binds, are lower. Given the roles of PV neurons in regulating DLPFC microcircuits and of PNNs in regulating PV cellular physiology, the identified alterations in PV neurons and their PNNs could contribute to DLPFC dysfunction in schizophrenia.

Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia

“…This hypothesis is based on findings that experimental manipulations in model systems which reduce glutamatergic drive to PV interneurons result in lower PV interneuron activity accompanied by lower expression of activity-dependent gene products (e.g., PV and the GABA-synthesizing enzyme glutamic acid decarboxylase 67, GAD67), abnormal gamma oscillations and working memory deficits(9-12). Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19). These deficits do not seem to be due to a global reduction in excitatory drive to all interneuron subtypes, as calretinin-containing (CR) interneurons, the most abundant interneuron subtype in the primate DLPFC(20), appear to be relatively unaffected in schizophrenia(15, 16, 21).…”

Age-Related Deterioration of Perineuronal Nets in the Primary Auditory Cortex of Mice

“…Deterioration of PNN may manifest as changes in intensity without a loss of PNN+ cell density (Enwright et al, 2016). To determine PNN intensity throughout A1 and at the single cell level, images were converted into 8-bit format (where 0 is total absence of PNN).…”

Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

“…For example, the decreased activity of pyramidal cells is thought to reduce excitation of parvalbumin basket (PVb) cells through various activity-dependent mechanisms involving GAD67, PV, Zif268, and PNNs. 216–219 Furthermore, dysregulated splicing of ERBB4 and lower expression of dysbindin may contribute to compromised excitatory drive to PVb cells. 220–222 Additional changes to GABA interneurons include deficits in PV chandelier cells (PVCh), SST, and CCK cells.…”