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 non-schizophrenic 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.

Fig. 1

Micrographs of segments of apical dendrites of layer III cortical pyramidal neurons. (A) Fetus at 33 weeks' gestation. Narrow dendrite with few immature, hair-like spines. (B,C) Thicker dendrite at 3 months postnatal with more bulbous spines. (D,E) Spine numerical density is highest at 5 months. (F) 21 months: spine density has fallen to perinatal levels. From Michel & Garey (1984).

Fig. 2

Layer III pyramidal neurons, Golgi method. (A) From a control brain, showing spiny dendrites. (B) Spineless segment of apical dendrite in a schizophrenic brain. (C) Higher power of spiny apical dendrite in a control brain. Scale bars: A: 25 μm; B: 15 μm; C: 10 μm.

Fig. 3

Scatter plots of spine numerical densities on layer III pyramidal apical dendrites from control and schizophrenic frontal and temporal cortex. Arrows indicate the mean for the blocks studied in each group.

Fig. 4

Micrograph of schizophrenic orbitofrontal cortex labelled for kainate receptor.

Fig. 5

GFAP staining for astroglia (A,B) and LN3 staining for microglia (C,D) in layer III of the temporal cortex of control (A,C) and schizophrenic (B,D) subjects. Scale bar = 40 μm. There is no obvious astrogliosis in schizophrenia, but there is microgliosis. From Radewicz et al. (2000).

Fig. 6

Significantly increased microglial numerical density in frontal and temporal, but not in cingulate, cortex in schizophrenia. Student's t-test for independent variables: *P < 0.05; **P < 0.01. From Radewicz et al. (2000).