Abstract
Background: Alterations in the subclass of cortical GABAergic interneurons that express the calcium-binding protein parvalbumin (PV) have been consistently reported in postmortem studies of schizophrenia. These alterations include lower messenger RNA (mRNA) and protein levels for PV and the GABA-synthesizing enzyme GAD1, as well as reduced expression of the potassium channel KCNS3, which is necessary for their characteristic fast-spiking properties. Moreover, tissue levels of mRNA for the activity-dependent transcriptional regulator EGR1 (Zif268), which is highly enriched in PV neurons, are also lower in schizophrenia. However, the molecular and anatomical phenotype of PV neuron pathology in schizophrenia remains incomplete.
Methods: To address this issue, we conducted the following studies of PV neurons in the postmortem prefrontal cortex from schizophrenia and comparison subjects. First, we examined the integrity of the perineuronal nets (PNNs) that surround PV cells. Second, we analyzed the transcriptome of PV cells captured by laser microdissection. Third, we evaluated the number of excitatory inputs to PV cells and the integrity of the ErbB4 signaling system that regulates the localization of PSD95 to excitatory synapses in PV neurons.
Results: In the prefrontal cortex, 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, are lower. Transcriptome profiling of laser-captured layer 3 PV neurons identified over 1000 genes that are differentially expressed in schizophrenia, most of which are not altered in layer 3 pyramidal neurons. Some of the alterations in PV neurons suggest a state of heightened plasticity, consistent with the alterations in PNNs, another plasticity regulator of PV cells. Finally, quantitative confocal immunocytochemical studies revealed that PV neurons receive fewer excitatory inputs in schizophrenia. This reduction appears to be attributable to altered splicing of ErbB4, which could disrupt the localization of PSD95 to excitatory synapses, selectively in PV neurons.
Conclusion: In concert, these findings provide new insights into the nature of PV neuron alterations in schizophrenia. Which of these findings represent a primary pathology of PV neurons and which are secondary in the disease process remain critical questions. Answers to these questions will inform which findings represent potential new targets for therapeutic interventions as well as how those targets should be attacked.