Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.

BACKGROUND: Up-regulation of gamma-aminobutyric acidA (GABAA) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development. METHODS: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA--expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 microns in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calcium-calmodulin-dependent protein kinase (CamIIK) were quantified. RESULTS: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics. CONCLUSIONS: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity-dependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression.

Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.

Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.

Cerebral brain metabolism in adult dyslexic subjects assessed with positron emission tomography during performance of an auditory task.

Ten dyslexic adults (aged 33.5 +/- 7.3 years, nine men, one woman) and 10 age-, sex- and handedness-matched control subjects (aged 33.6 +/- 5.8 years) performed an auditory syllable discrimination task during 18-fluoro-2-deoxyglucose uptake, and then underwent positron emission tomographic scans. A second normal control group performed an analogous visual discrimination task. Dyslexic subjects experienced greater difficulty and made significantly more errors in performing the auditory task. There were no differences in brain metabolic rates in lateral cortical areas (frontal, parietal, temporal, and occipital lobes). A significant difference emerged in the medial temporal lobe, with dyslexic subjects having significantly higher absolute and relative brain metabolism along an anterior-posterior gradient than normal adults. These data support the hypothesis of altered cerebral processing of auditory stimuli in patients with dyslexia.

Comparison of regional brain metabolism in bulimia nervosa and affective disorder assessed with positron emission tomography.

Women with bulimia often present with symptoms of depression in addition to bingeing and purging behavior. Brain metabolism in eight women with bulimia nervosa was compared to that in eight women with major affective disorder and eight normal women, using positron emission tomography and 18-fluoro-2-deoxyglucose. Normal women have higher right than left cortical metabolic rates and active basal ganglia. Bulimics lost the normal right activation in some areas, but maintained basal ganglia activity. Depressives retained right hemisphere activation, but had decreased metabolism in basal ganglia. This suggests that although women with bulimia frequently present with symptoms of depression, the pathophysiologic changes associated with bulimia differ from major effective disorder.