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Abstract The cell adhesion molecule neuroplastin (Np) is a novel candidate to influence human intelligence. Np-deficient mice display complex cognitive deficits and reduced levels of Plasma Membrane Ca2+ ATPases (PMCAs), an essential regulator of the intracellular Ca2+ concentration ([iCa2+]) and neuronal activity. We show abundant expression and conserved cellular and molecular features of Np in glutamatergic neurons in human hippocampal-cortical pathways as characterized for the rodent brain. In Nptn lox/loxEmx1Cre mice, glutamatergic neuron-selective Np ablation resulted in behavioral deficits indicating hippocampal, striatal, and sensorimotor dysfunction paralleled by highly altered activities in hippocampal CA1 area, sensorimotor cortex layers I-III/IV, and the striatal sensorimotor domain detected by single-photon emission computed tomography. Altered hippocampal and cortical activities correlated with reduction of distinct PMCA paralogs in Nptn lox/loxEmx1Cre mice and increased [iCa2+] in cultured mutant neurons. Human and rodent Np enhanced the post-transcriptional expression of and co-localized with PMCA paralogs in the plasma membrane of transfected cells. Our results indicate Np as essential for PMCA expression in glutamatergic neurons allowing proper [iCa2+] regulation and normal circuit activity. Neuron-type-specific Np ablation empowers the investigation of circuit-coded learning and memory and identification of causal mechanisms leading to cognitive deterioration.

The purpose of this focused review is to present and discuss recent data on the changing organization of cerebral midline structures that support the growth and development of the largest commissure in humans, the corpus callosum. We will put an emphasis on the callosal growth during the period between 20 – 45 postconceptual weeks (PCW) and focus on the advantages of a correlated histological/magnetic resonance imaging (MRI) approach. The midline structures that mediate development of the corpus callosum in rodents, also mediate its early growth in humans. However, later phases of callosal growth in humans show additional medial transient structures: grooves made up of callosal septa and the subcallosal zone. These modular (septa) and laminar (subcallosal zone) structures enable the growth of axons along the ventral callosal tier after 18 PCW, during the rapid increase in size of the callosal midsagittal cross-section area. Glial fibrillary acidic protein positive cells, neurons, guidance molecule semaphorin3A in cells and extracellular matrix (ECM), and chondroitin sulfate proteoglycan in the ECM have been identified along the ventral callosal tier in the protruding septa and subcallosal zone. Postmortem MRI at 3 Tesla can demonstrate transient structures based on higher water content in ECM, and give us the possibility to follow the growth of the corpus callosum in vivo, due to the characteristic MR signal. Knowledge about structural properties of midline morphogenetic structures may facilitate analysis of the development of interhemispheric connections in the normal and abnormal fetal human brain.

IntroductionAdversities during the perinatal period can decrease oxygen supply to the fetal brain, leading to various hypoxic brain injuries, which can compromise the regularity of brain development in different aspects. To examine the catecholaminergic contribution to the link between an early-life hypoxic insult and adolescent behavioral aberrations, we used a previously established rat model of perinatal hypoxia but altered the hypobaric to normobaric conditions.MethodsExploratory and social behavior and learning abilities were tested in 70 rats of both sexes at adolescent age. Inherent vertical locomotion, sensory-motor functions and spatial learning abilities were explored in a subset of animals to clarify the background of altered exploratory behavior. Finally, the concentrations of dopamine (DA) and noradrenaline in midbrain and pons, and the relative expression of genes for DA receptors D1 and D2, and their down-stream targets (DA- and cAMP-regulated phosphoprotein, Mr 32 kDa, the regulatory subunit of protein kinase A, and inhibitor-5 of protein phosphatase 1) in the hippocampus and thalamus were investigated in 31 rats.ResultsA lesser extent of alterations in exploratory and cognitive aspects of behavior in the present study suggests that normobaric conditions mitigate the hypoxic injury compared to the one obtained under hypobaric conditions. Increased exploratory rearing was the most prominent consequence, with impaired spatial learning in the background. In affected rats, increased midbrain/pons DA content, as well as mRNA levels for DA receptors and their down-stream elements in the thalamus, but not the hippocampus, were found.ConclusionWe can conclude that a mild hypoxic event induced long-lasting disbalances in mesothalamic DA signaling, contributing to the observed behavioral alterations. The thalamus was thereby indicated as another structure, besides the well-established striatum, involved in mediating hypoxic effects on behavior through DA signaling.