Altered Gradients of Glutamate and Gamma-Aminobutyric Acid Transcripts in the Cortical Visuospatial Working Memory Network in Schizophrenia

Abstract

Background: Visuospatial working memory (vsWM), which is impaired in schizophrenia, requires information transfer across multiple nodes in the cerebral cortex, including visual, posterior parietal, and dorsolateral prefrontal regions. Information is conveyed across these regions via the excitatory projections of glutamatergic pyramidal neurons located in layer 3, whose activity is modulated by local inhibitory gamma-aminobutyric acidergic (GABAergic) neurons. Key properties of these neurons differ across these cortical regions. Consequently, in schizophrenia, alterations in the expression of gene products regulating these properties could disrupt vsWM function in different ways, depending on the region(s) affected.

Methods: Here, we quantified the expression of markers of glutamate and GABA neurotransmission selectively in layer 3 of four cortical regions in the vsWM network from 20 matched pairs of schizophrenia and unaffected comparison subjects.

Results: In comparison subjects, levels of glutamate transcripts tended to increase, whereas GABA transcript levels tended to decrease, from caudal to rostral, across cortical regions of the vsWM network. Composite measures across all transcripts revealed a significant effect of region, with the glutamate measure lowest in the primary visual cortex and highest in the dorsolateral prefrontal cortex, whereas the GABA measure showed the opposite pattern. In schizophrenia subjects, the expression levels of many of these transcripts were altered. However, this disease effect differed across regions, such that the caudal-to-rostral increase in the glutamate measure was blunted and the caudal-to-rostral decline in the GABA measure was enhanced in the illness.

Conclusions: Differential alterations in layer 3 glutamate and GABA neurotransmission across cortical regions may contribute to vsWM deficits in schizophrenia.

Keywords: GABA; Glutamate; Prefrontal cortex; Schizophrenia; Visual cortex; Working memory.

Figure 1. Sampling of cortical regions and layer 3

(A) Schematic drawings of the medial and lateral surfaces of the right hemisphere of the human brain (top). Vertical lines indicate the approximate locations of the coronal sections (bottom). Locations of cortical regions of the vsWM network selected for sampling are shaded. Arrows labeled dorsal, medial, ventral, and lateral refer to the coronal sections (B) Representative Nissl-stained sections illustrating the laminar borders (dashed lines) and the borders as drawn of layer 3 for laser microdissection in each region. Numbers indicate cortical layers. V1, primary visual cortex; V2, association visual cortex; PPC, posterior parietal cortex; DLPFC, dorsolateral prefrontal cortex; sfs, superior frontal sulcus; ips, intraparietal sulcus; cs, calcarine sulcus.

Figure 2. Glutamate and GABA transcript levels in layer 3 across cortical regions of the vsWM network in unaffected comparison subjects

For each panel (A-I), target transcript name is at the top center and ANCOVA results for the effect of region at the top right. Individual subjects are shown by the same symbol in all graphs. Horizontal bars represent group means. Regions within each graph that do not share the same letter are significantly different (p<0.05). V1, primary visual cortex; V2, association visual cortex; PPC, posterior parietal cortex; DLPFC, dorsolateral prefrontal cortex.

Figure 3. Effect of schizophrenia on glutamate and GABA transcript levels across cortical regions of the vsWM network

For each panel (A-I), target transcript name is at the top center. Individual subjects are shown by the same symbol in all graphs. Horizontal bars represent mean percent difference (schizophrenia – unaffected comparison subject). V1, primary visual cortex; V2, association visual cortex; PPC, posterior parietal cortex; DLPFC, dorsolateral prefrontal cortex.

Figure 4. Effect of schizophrenia on composite measures of glutamate and GABA transcripts in the vsWM network

In unaffected comparison subjects, the composite A) glutamate (F_3,114=14.5, p<0.001) and B) GABA (F_3,114=5.4, p=0.002) measures showed significant, and opposite, caudal-to-rostral gradients. Note that in the schizophrenia subjects, this gradient was lost for the glutamate measure (F_3,114=1.3, p=0.28), but was more highly significant for the GABA measure (F_3,114=15.8, p<0.001). Accordingly, the region-by-diagnosis interaction was significant for the glutamate (F_3,114=5.1, p=0.002), but not for the GABA (F_3,114=1.7, p=0.18), composite measure. V1, primary visual cortex; V2, association visual cortex; PPC, posterior parietal cortex; DLPFC, dorsolateral prefrontal cortex.