Altered Distribution of Nicotinamide-Adenine Dinucleotide Phosphate—Diaphorase Cells in Frontal Lobe of Schizophrenics Implies Disturbances of Cortical Development

TLDR

Epidemiological and anatomical studies suggest that disturbances in brain development, particularly altered neuronal migration, may contribute to schizophrenia by disrupting cortical connectivity and associative function. The study aimed to examine nicotinamide‑adenine dinucleotide phosphate‑diaphorase‑positive neurons in the prefrontal cortex and underlying white matter of matched schizophrenic and control brains. The authors performed histochemical staining for NADPH‑diaphorase on matched brain sections to characterize this neuronal population. Schizophrenic dorsolateral prefrontal cortex showed a significant decline of NADPH‑diaphorase neurons in superficial white matter and cortex, but an increase deeper than 3 mm, indicating a subplate disturbance that compromises programmed cell death and neuronal migration, potentially disrupting frontal lobe connectivity.

Abstract

• 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<i>subplate</i>, 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.