Distorted Distribution of Nicotinamide-Adenine Dinucleotide Phosphate—Diaphorase Neurons in Temporal Lobe of Schizophrenics Implies Anomalous Cortical Development

Abstract

The distribution of neurons expressing the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) in the lateral and medial temporal lobes of schizophrenic and matched control brains was investigated in a systematic blind analysis. Schizophrenics had significantly lower numbers of NADPH-d neurons in the hippocampal formation and in the neocortex of the lateral temporal lobe but significantly greater numbers of NADPH-d neurons in the white matter of the lateral temporal lobe and a tendency toward greater numbers in parts of the parahippocampal white matter. The distorted distribution of NADPH-d neurons in the lateral temporal lobe, which may be explained by developmental disturbances, such as impaired neuronal migration or an alteration in the death cycle of transitory subcortical neurons, is similar to that found in the prefrontal cortex of schizophrenics. Alterations of cortical ontogenesis, as reflected in the distribution of NADPH-d neurons, appear to be widespread among neocortical association fields in schizophrenics and may provide a clue to the cause of the disease.

Neonatal Nonhandling andIn UteroPrenatal Stress Reduce the Density of NADPH-Diaphorase-Reactive Neurons in the Fascia Dentata and Ammon’s Horn of Rats

“…Temporal lobe (including the hippocampus and parahippocampal region) neuropathology has been the most consistent anatomical finding in the brains of schizophrenics (e.g., Scheibel and Kovelman, 1981;Kovelman and Scheibel, 1986;Altshulter et al, 1987;Roberts, 1991;Roberts and Horton, 1992), and it has been suggested that such an abnormality may be developmental in nature (Weinberger, 1987;Jaskiw and Weinberger, 1992;Lipska et al, 1993). In particular, significant alteration in the distribution of NADPH-d-reactive neurons has been reported in the temporal lobes of schizophrenic patients (Akbarian et al, 1993). Our present results thus lend support to the suggestion that early manipulations such as prenatal stress or neonatal nonhandling may provide a neurodevelopmental model of schizophrenia (Feldon and Weiner, 1992).…”

Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia

“…However, the fact that thalamocortical tracts form early in development suggests that this abnormality could already be present at birth or in the first years of life and would be consistent with the neurodevelopmental nature of schizophrenia. Indeed, there is evidence for altered interstitial prefrontal neurons, considered remnants of the subplate (Kostovic et al, 2011), in schizophrenia (Akbarian et al, 1993;Anderson et al, 1996;Harrison, 2003, 2005;Kirkpatrick et al, 2003;Yang et al, 2011), supporting an early pathological process. Furthermore, as the PFC completes maturation well after the thalamocortical fibers have reached the subplate (Kostovic and Judas, 2010), it is conceivable that thalamic neuronal activity might be a potential effector of PFC maturation and developing function via its connectivity (Kanold, 2009).…”

Cytokine and growth factor involvement in schizophrenia—support for the developmental model

“…15,16 The corticolimbic system can exhibit a number of alterations, including reduced number of pyramidal neurons in the hippocampus and interneurons in the cingulate cortex, cytoarchitectonic abnormalities in the entorhinal cortex, altered orientation of hippocampal pyramidal cells as well as enlarged ventricles. [9][10][11][16][17][18][19] Some patients also exhibit reduction of interneurons and an increased number of apical dendrites in layer II of the prefrontal cortex. 17 Moreover, disorientation of pre-alpha cells in layer II of the entorhinal cortex suggests a problem with embryonic neuroblast migration and/or differentiation.…”

“…Some abnormalities in schizophrenic brain have been attributed to abnormal migration of interneurons from the cortical subplate. 15,16,64 During neocortical development, subplate cells express the neuropeptides somatostatin and neuropeptide Y, and form active synapses that regulate the subsequent formation of cortical layers and thalamocortical circuits. 65 Later in development, most subplate cells undergo apoptosis, disappearing by adulthood.…”