Transcriptional profiling of parvalbumin interneurons from dorsolateral prefrontal cortex in schizophrenia
Murray KD, Akil H, Barchas JD, Bunney WE, Myers RM, Schatzberg AF, Watson SJ, Jones EG
Society for Neuroscience. 2011.
Disorders of cognitive function in schizophrenia have been attributed to an altered balance of cortical excitation and inhibition manifested as altered cortical synchrony. The parvalbumin (PV) subclass of cortical inhibitory interneurons is implicated in the pathophysiology of schizophrenia. Using laser capture microscopy (LCM) and high density microarray analysis we examined gene expression in parvalbumin neurons of dorsolateral prefrontal cortex (DLPFC) in postmortem brains from schizophrenics and age matched controls. We used Wisteria floribunda (WF) lectin to label glycoproteins surrounding parvalbuminergic cortical interneurons. Greater than 95% of WF positive cells co-expressed parvalbumin. Using a novel rapid WF histological preparation, total RNA was isolated from LCM acquired cells and amplified using NuGEN’s SPIA technology. Semiquantitative real-time PCR analysis confirmed RNA from LCM isolated cells was enriched for parvalbumin (> 6 fold) compared with calbindin or calretinin which identify other subsets of inhibitory interneurons. Expression of glutamic acid decarboxylase 67 (GAD67) mRNA was 15-fold greater than the alpha subunit of CaMKII, a marker of glutamatergic neurons. To measure global patterns of transcriptional change in PV neurons in schizophrenia, RNA from LCM isolated cells was amplified and hybridized to Affymetrix U133 Plus 2.0 microarrays. Preliminary analysis revealed significant differences in expression of transcripts related to glutamate or GABA neurotransmission. Decreases in GAD67 and GABA(A) receptor alpha(1) subunit mRNAs were consistent with previous reports in postmortem studies. Increased expression of GABA(A) receptor beta(2) subunit mRNA, a potential susceptibility marker for schizophrenia, was also observed. Significantly overrepresented networks of expressed genes were those associated with cell-cell signaling and communication, including genes linked with regulation of synaptic number and/or transmission. This cell type specific microarray analysis may identify novel pathological insults in schizophrenia not seen by heterogeneous cell type analyses.