When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits

Abstract

Schizophrenia probably has a developmental origin. This review refers to three of our published series of studies related to this hypothesis: loss of dendritic spines on cerebral neocortical pyramidal neurons, decreased numerical density of glutamatergic neurons, and microgliosis. First, brains of schizophrenic patients and nonschizophrenic controls were obtained post mortem and blocks of multiple cortical areas impregnated with a Rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons of which the soma was in layer III (which takes part in corticocortical connectivity) and which met strict criteria for impregnation quality. Data were obtained blind: diagnoses were only revealed by a third party after measurements were completed. The mean spine count in all cortical areas studied in the control series was 243 mm )1 of dendrite and in the schizophrenics 108. Measurements in frontal and temporal association cortex showed the greatest reduction in spine number in schizophrenia (299 in control frontal cortex and 101 in schizophrenics, and 276 mm )1 in control temporal cortex and 125 in schizophrenics). There was no correlation of spine loss with age at death. Our results support the concept of a neurodevelopmental defect in the neuropil affecting glutamatergic neurons in schizophrenia and may help to explain loss of cortical volume without loss of neurons. In a second part of our study we used an antibody to the kainate receptor subunit GluR 5 ⁄ 6 ⁄ 7 and showed a decrease in numerical density of presumed glutamatergic neurons in schizophrenic orbitofrontal cortex. Finally, as glia play a major role in the developing nervous system, we investigated whether schizophrenia was associated with glial changes in frontal and temporal cortex. Astroglia and microglia were identified in schizophrenic and control brains, using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR), respectively. Significant increases were found in microglial numerical density in schizophrenics compared with controls: 28% in frontal area 9 (115 cells mm )2 compared with 89), and a 57% increase in temporal area 22(139 cells mm )2 compared with 88). For both areas, astroglia showed no significant differences between schizophrenics and controls. No significant differences were found in cortical thickness or total neuronal numerical density between the two groups. This specific increase in numerical density of microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, could be related to possible changes in cortical neuropil architecture as revealed by loss of dendritic spines.

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

“…Reductions in neuron density in the primary visual cortex (Dorph-Petersen et al, 2007) and reduced glutamatergic neurons in the orbitofrontal cortex have been reported (Garey, 2010). Presently, the DISC1 status of the patients reported in those studies is unknown.…”

The Methylazoxymethanol Acetate (MAM-E17) Rat Model: Molecular and Functional Effects in the Hippocampus

“…Not all of the molecular changes observed in hippocampi of schizophrenia patients have been detected in the MAM rats (Eastwood et al, 1995a;Eastwood and Harrison, 1998;Fatemi et al, 2000), although the same pathways and cellular functions were found to be affected, as identified by in silico pathway analysis and supported by TAC analysis. Such molecular changes may result from a decreased number of total synapses, defective synaptic coupling, or a change in the neuropil formation, as suggested by Matricon et al (2010) for the MAM-E17 model and demonstrated in cases of human schizophrenia subjects (Garey, 2010).…”

“…Nevertheless, the origin of these changes in the hippocampus is unclear. LC-MS E profiling of whole hippocampal tissue as used here does not take into account cell morphological and subfield-specific expression differences as seen in schizophrenia studies (Benes et al, 1991;Eastwood et al, 1995b;Gao et al, 2000;Garey, 2010;Knable et al, 2004). Therefore, we suggest that future studies should investigate subcellular and subregional expression and phophorylation patterns of synaptic markers and glutamatergic indices, as identified in this study, in combination with synaptic structure and density measurements in hippocampal subfields of the MAM-E17 rat model.…”

Early Prefrontal Functional Blockade in Rats Results in Schizophrenia-Related Anomalies in Behavior and Dopamine

“…In the past two decades, several studies have described cytoarchitectural and neuronal morphometric abnormalities consistent with defects in early neurodevelopment at the level of the PFC, particularly in the left hemisphere (Kalus et al, 2000;Garey, 2010;Yang et al, 2011). In schizophrenia, miswiring of neuronal connections due at least in some cases to neurodevelopmental failures would result in disconnectivity between different integrative brain regions, especially the PFC, temporal lobe, and striatal regions (Lawrie et al, 2002;Stephan et al, 2009).…”