Schizophrenia is one of the most widespread and complex mental disorders. To characterize the impact of schizophrenia, we performed single-nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. In addition, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most marked in upper-layer GABAergic neurons, including down-regulation in energy metabolism and up-regulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Last, Visium spatial transcriptomics further corroborated upper-layer neuron vulnerability in schizophrenia. Overall, our results point toward general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology.
Cell‐adhesion glycoprotein neuroplastin (Np) is involved in the regulation of synaptic plasticity and balancing hippocampal excitatory/inhibitory inputs which aids in the process of associative memory formation and learning. Our recent findings show that neuroplastin expression in the adult human hippocampus is specifically associated with major hippocampal excitatory pathways and is related to neuronal calcium regulation. Here, we investigated the hippocampal expression of brain‐specific neuroplastin isoform (Np65), its relationship with amyloid and tau pathology in Alzheimer's disease (AD), and potential involvement of neuroplastin in tissue response during the disease progression. Np65 expression and localization was analysed in six human hippocampi with confirmed AD neuropathology, and six age‐/gender‐matched control hippocampi by imunohistochemistry. In AD cases with shorter disease duration, the Np65 immunoreactivity was significantly increased in the dentate gyrus (DG), Cornu Ammonis 2/3 (CA2/3), and subiculum, with the highest level of Np expression being located on the dendrites of granule cells and subicular pyramidal neurons. Changes in the expression of neuroplastin in AD hippocampal areas seem to be related to the progression of disease. Our study suggests that cell‐adhesion protein neuroplastin is involved in tissue reorganization and is a potential molecular marker of plasticity response in the early neurodegeneration process of AD.
AimTo analyze postnatal development and life-span changes of apical dendrite side branches (oblique dendrites) from associative layer IIIC magnopyramidal neurons in the human dorsolateral prefrontal cortex and to compare the findings with the previously established pattern of basal dendrite development.MethodsWe analyzed dendritic morphology from 352 rapid-Golgi impregnated neurons (10-18 neurons per subject) in Brodmann area 9 from the post-mortem tissue of 25 subjects ranging in age from 1 week to 91 years. Data were collected in the period between 1994 and 1996, and the analysis was performed between September 2017 and February 2018. Quantitative dendritic parameters were statistically analyzed using one-way analysis of variance and two-tailed t tests.ResultsOblique dendrites grew rapidly during the first postnatal months, and the increase in the dendrite length was accompanied by the outgrowth of new dendritic segments. After a more than one-year-long “dormant” period of only fine dendritic rearrangements (2.5-16 months), oblique dendrites displayed a second period of marked growth, continuing through the third postnatal year. Basal and oblique dendrites displayed roughly the same growth pattern, but had considerably different topological organization in adulthood.ConclusionOur analysis confirmed that a biphasic pattern of postnatal dendritic development, together with a second growth spurt at the age of 2-3 years, represents a unique feature of the associative layer IIIC magnopyramidal neurons in the human dorsolateral prefrontal cortex. We propose that these structural changes relate to rapid cognitive development during early childhood.
Anxiety disorders are the most frequent mental disorders and are more prevalent in the female population. Up to date, an involvement of guanylate cyclase A and B in anxiety‐like behavior has been suggested. In this study, we showed an expression of guanylate cyclase C (GC‐C) in the amygdala which is regulated by feeding. Therefore, we further investigated sex differences of GC‐C effects on anxiety levels with special attention to female estrous cycle and feeding. The effects of estrous cycle and feeding were investigated by several behavior tests: elevated plus maze, home cage escape and novelty‐induced hypophagy. Possible changes in GC‐C expression in amygdala and hypothalamus during estrous cycle were established by qPCR. When GC‐C is activated (after a meal), the sex difference in all behavior tests used was abolished. As the expression of mRNA for GC‐C in the amygdala increases 2 hr after a meal only in female animals, the anxiety levels change after a meal again only in female animals. When the anxiety levels are investigated, it is very important to pay attention not only to estrous cycle in female animals but also when animals were fed compared to the time point of the experiments. Concluding from our results, the sex differences in the incidence of anxiety disorders in humans could be GC‐C dependent.
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