Developing brain under renewed attack: viral infection during pregnancy

Living in a globalized world, viral infections such as CHIKV, SARS-COV-2, and ZIKV have become inevitable to also infect the most vulnerable groups in our society. That poses a danger to these populations including pregnant women since the developing brain is sensitive to maternal stressors including viral infections. Upon maternal infection, the viruses can gain access to the fetus via the maternofetal barrier and even to the fetal brain during which factors such as viral receptor expression, time of infection, and the balance between antiviral immune responses and pro-viral mechanisms contribute to mother-to-fetus transmission and fetal infection. Both the direct pro-viral mechanisms and the resulting dysregulated immune response can cause multi-level impairment in the maternofetal and brain barriers and the developing brain itself leading to dysfunction or even loss of several cell populations. Thus, maternal viral infections can disturb brain development and even predispose to neurodevelopmental disorders. In this review, we discuss the potential contribution of maternal viral infections of three relevant relative recent players in the field: Zika, Chikungunya, and Severe Acute Respiratory Syndrome Coronavirus-2, to the impairment of brain development throughout the entire route

Expression patterns of semaphorin7A and plexinC1 during rat neural development suggest roles in axon guidance and neuronal migration

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A Potential Regulatory Role for Intronic microRNA-338-3p for Its Host Gene Encoding Apoptosis-Associated Tyrosine Kinase

MicroRNAs (miRNAs) are important gene regulators that are abundantly expressed in both the developing and adult mammalian brain. These non-coding gene transcripts are involved in post-transcriptional regulatory processes by binding to specific target mRNAs. Approximately one third of known miRNA genes are located within intronic regions of protein coding and non-coding regions, and previous studies have suggested a role for intronic miRNAs as negative feedback regulators of their host genes. In the present study, we monitored the dynamic gene expression changes of the intronic miR-338-3p and miR-338-5p and their host gene Apoptosis-associated Tyrosine Kinase (AATK) during the maturation of rat hippocampal neurons. This revealed an uncorrelated expression pattern of mature miR-338 strands with their host gene. Sequence analysis of the 3′ untranslated region (UTR) of rat AATK mRNA revealed the presence of two putative binding sites for miR-338-3p. Thus, miR-338-3p may have the capacity to modulate AATK mRNA levels in neurons. Transfection of miR-338-3p mimics into rat B35 neuroblastoma cells resulted in a significant decrease of AATK mRNA levels, while the transfection of synthetic miR-338-5p mimics did not alter AATK levels. Our results point to a possible molecular mechanism by which miR-338-3p participates in the regulation of its host gene by modulating the levels of AATK mRNA, a kinase which plays a role during differentiation, apoptosis and possibly in neuronal degeneration

Deciphering serotonin's role in neurodevelopment

One of the most challenging questions in neurobiology to tackle is how the serotonergic system steers neurodevelopment. With the increase in serotonergic anxiolytic and antidepressant drugs, serotonin was thought to signal adversity or to serve as an emotional signal. However, a vast amount of literature is accumulating showing that serotonin rather mediates neuroplasticity and plays a key role in early developmental processes. For instance, selective serotonin reuptake inhibitors (SSRIs), serving as antidepressants, increase neurogenesis and trigger autism-related brain and behavioural changes during embryonic and perinatal exposure. Moreover, serotonin transporter gene variation is associated with alterations in corticolimbic neuroplasticity, autism-related neuroanatomical changes, as well alterations in social behaviour. Hence, the view is emerging that early life changes in serotonin levels influence the developmental course of socio-emotional brain circuits that are relevant for autism and other neurodevelopmental disorders. It is particularly exciting that the effects of embryonic and perinatal SSRI exposure and serotonin transporter gene variation on neurodevelopment seem to overlap to a large extent, at the cellular as well as the behavioural level. Yet, the precise mechanisms by which serotonin mediates neurodevelopment in the normal and ´autistic´ brain is unclear. Whereas serotonin has a placental origin during early gestation, serotonergic neurons develop during midgestation under the control of a cascade of transcription factors determining the fate of mid-hindbrain neurons that together for the Raphe nuclei. These neurons are among the earliest neurons to be generated, and because serotonin is released before any conventional synapses are formed, serotonin is suspected to influence crucial neurodevelopmental processes such as proliferation,migration and network formation. During late gestation they target their final destinations in, for instance, the cortex, where they affect the secretion of reelin. Reelin is a secreted extracellular matrix glycoprotein that helps to regulate processes of neuronal migration and positioning in the developing cortex by controlling cell–cell interactions. During the late prenatal and early postnatal phase (in rodents) serotonin further shapes the outgrowth of projecting neurons, synaptic connectivity, and the morphology of white fiber tracts. This is under the influence of transient serotonin transporter expression in (thalamo)cortical projections, sensory and prefrontal cortices and the hippocampus, as well as the local expression patterns of 5-HT1A, 5-HT1B and 5-HT3A receptors that each exert their specific roles in neuronal migration, remodeling of axons, and controlling dendritic complexity. There is also evidence that serotonin influences neural activity in locus ceroeleus neurons. Hence, serotonin appears to influence the development of both short- and long-distance connections in the brain. This Research Topic is devoted to studies pinpointing the neurodevelopmental effects of serotonin in relation to prenatal SSRI exposure, serotonin transporter gene variation, and autism/neurodevelopmental disorders, using a wide-variety of cellular and molecular neurobiological techniques like, (epi)genetics, knockout, knockdown, neuroanatomy, physiology, MRI and behaviour in rodents and humans. We especially encouraged attempts to cross-link the neurodevelopmental processes across the fields of prenatal SSRI exposure, serotonin transporter gene variation, and autism/neurodevelopmental disorders, as well as new views on the positive or beneficial effects on serotonin-mediated neurodevelopmental changes

Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling

Eph receptors are widely expressed during cerebral cortical development, yet a role for Eph signaling in the generation of cells during corticogenesis has not been shown. Cortical progenitor cells selectively express one receptor, EphA4, and reducing EphA4 signaling in cultured progenitors suppressed proliferation, decreasing cell number. In vivo, EphA4-/- cortex had a reduced area, fewer cells and less cell division compared with control cortex. To understand the effects of EphA4 signaling in corticogenesis, EphA4-mediated signaling was selectively depressed or elevated in cortical progenitors in vivo. Compared with control cells, cells with reduced EphA4 signaling were rare and mitotically inactive. Conversely, overexpression of EphA4 maintained cells in their progenitor states at the expense of subsequent maturation, enlarging the progenitor pool. These results support a role for EphA4 in the autonomous promotion of cell proliferation during corticogenesis. Although most ephrins were undetectable in cortical progenitors, ephrin B1 was highly expressed. Our analyses demonstrate that EphA4 and ephrin B1 bind to each other, thereby initiating signaling. Furthermore, overexpression of ephrin B1 stimulated cell division of neighboring cells, supporting the hypothesis that ephrin B1-initiated forward signaling of EphA4 promotes cortical cell division

Perturbed Developmental Serotonin Signaling Affects Prefrontal Catecholaminergic Innervation and Cortical Integrity

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Expression patterns of and during rat neural development suggest roles in axon guidance and neuronal migration-6

<p><b>Copyright information:</b></p><p>Taken from "Expression patterns of and during rat neural development suggest roles in axon guidance and neuronal migration"</p><p>http://www.biomedcentral.com/1471-213X/7/98</p><p>BMC Developmental Biology 2007;7():98-98.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2008261.</p><p></p>ex and striatum. Dorsal is to the top. (A, B) At E19, and are expressed in the cortical plate (CP), whereas is also expressed in the subplate (SP). In the postnatal (C, D) and adult cortex (E, F), and can be found in layers II–VI. Note that expression is highest in layers II and III in the adult (E). (G, H) Low magnification overview of and expression in the adult brain. Note that cortical expression is most pronounced within the barrel area of the presumptive somatosensory cortex (arrows indicate the anterior to posterior limits of the barrel cortex within layer V). In addition, is strongly expressed in the subiculum (S), hippocampus (Hip), striatum (Str) and thalamus (Th). (I-L) is expressed in a mediolateral gradient within the developing (I) and adult (J) striatum. Interestingly, is expressed in a lateromedial gradient in the embryonic (J) but not adult (L) striatum. 7A, Sema7A; C1, plexinC1; cc, corpus callosum; CX, cortex; GP, globus pallidus; IC, inferior colliculus; SSZ, striatal subventricular zone. Scale bar 140 μm (A, B), 120 μm (C, D), 2.2 mm (E, F), 17 mm (G, H), 180 μm (I, J), and 1.3 mm (K, L)

Expression patterns of and during rat neural development suggest roles in axon guidance and neuronal migration-5

<p><b>Copyright information:</b></p><p>Taken from "Expression patterns of and during rat neural development suggest roles in axon guidance and neuronal migration"</p><p>http://www.biomedcentral.com/1471-213X/7/98</p><p>BMC Developmental Biology 2007;7():98-98.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2008261.</p><p></p>coronal sections of the adult meso-diencephalic dopamine (mdDA) system. A, C and E show consecutive sections of the rostral part of mdDA system, B, D and F of its caudal part. Dorsal is to the top. (A, B) labels mdDA neurons in the subtantia nigra (SN) and ventral tegmental area (VTA). Arrows in A through F outline the position of the SN as visualized by TH labeling. Arrowheads in B, D and F indicate the central part of the VTA. (A-F) Note that whereas overlap in and expression is largely confined to the lateral aspect of the SN (C, D), and predominantly overlap in the central part of the VTA (F, indicated by arrowhead). No expression is detected in the SN (E, F). Asterisk indicates the fasciculus retroflexus. (G, H) Colocalization of TH protein (brown) and (G; purple) in the SN and of TH protein (brown) and (H; purple) in the VTA reveals or -positive mdDA neurons (red arrows in G, H), mdDA neurons that lack these transcripts (arrowheads in G, H), and non-mdDA neurons or cells that express or (black arrows in G, H). 7A, Sema7A; C1, plexinC1; fr, fasciculus retroflexus; mt, mammillothalamic tract; pc, pars compacta; pr, pars reticulare. Scale bar 250 μm (A-F), and 65 μm (G, H)