Evaluation of molecular, cellular and behavioral consequences of serotonin 1A receptor deletion

In 1998, three different research groups simultaneously reported increased anxiety-related behavior in tests of conflict in their serotonin 1a (5-HT1a) receptor knockout (KO) line with male mice being more severely affected by 5-HT1a receptor deletion than female KO. Similarly, in the hippocampus, we observed increased dendritic complexity in the stratum radiatum of CA1 pyramidal neurons in male but not in female 5-HT1a receptor KO mice. These observations prompted us to investigate gender- dependent differences of 5-HT1a receptor deletion in hippocampal-related behavioral tasks. Testing our mice in anxiety-related paradigms, we reproduced the original studies showing increased anxiety- related behavior in male 5-HT1a receptor KO mice when compared to male WT mice, but no difference between female 5-HT1a receptor KO and WT mice. Similarly, male 5-HT1a receptor KO mice were impaired in association of aversive stimuli fear conditioning paradigms. We argue that increased dendritic complexity and increased synaptic strength of CA3-CA1 synapses in the stratum radiatum impaired proper signal propagation attributed to overactivation of CA1 pyramidal neurons leading to impaired fear memory of male 5-HT1a receptor KO mice. Similar mechanisms in the ventral hippocampus are likely to have contributed to gender-dependent differences in anxiety-related behavior in our and the original studies from 1998. In this study, we started to shed light on the 5-HT1a receptor downstream signaling pathways involved in dendritogenesis of pyramidal neurons during early postnatal development. We could show that NR2B-containing NMDA receptor during development acts downstream of 5-HT1a receptor and is responsible for increased amount of branching in male 5-HT1a receptor KO mice. Conversely, protein and NR2B mRNA expression was increased in 5-HT1a receptor KO mice at P15. Although the exact signaling cascade of 5-HT1a receptor regulating NR2B-containing NMDA receptor has not been determined, CaMKII is a potential downstream effector to influence transportation and removal of NR2B-containing NMDA receptors to and from the synapse. In contrast, Erk1/2 likely acts downstream of NR2B-containing NMDA receptors and was shown to be sufficient to regulate dendritic branching. Moreover, increased NR2B-containing NMDA receptor mediated cell death via excitotoxicity during development and is likely to be involved in reduced survival of adult born neurons in the hippocampus of 5-HT1a receptor KO male. The convergence of 5-HT1a receptor signaling onto NR2B-containing NMDA receptor signaling enables estrogen to interfere with its downstream pathway via G-protein coupled estrogen receptor 1 activation resulting in normalization of branching and behavior in female 5-HT1a receptor mice. In conclusion, our data strongly suggests a hormone- regulated mechanism that by converging on NR2B-containing NMDA receptor signaling is able to normalize morphology of pyramidal neurons and behavior of female 5-HT1a receptor KO mice. Our findings provide a possible explanation for gender-dependent differences in the occurrence of mental disorders with 5-HT1a receptor abnormalities as a strong predisposing factor. -- En 1998, trois équipes de recherche ont décrit un comportement de type anxieux dans des tests de conflit pour leur souris transgéniques avec une délétion du gène pour le récepteur 5-HT1a de la sérotonine. De plus, les trois groupes rapportent un phénotype plus sévère pour le comportement anxieux chez les souris transgéniques mâles que femelles. Dans l'hippocampe, la région avec la densité de récepteur 5-HT1a la plus élevée dans le télencéphale, nous avons observé dans le stratum radiatum une complexité accrue des arborisations dendritiques des neurones pyramidaux du secteur CA1 chez les souris transgénique mâles mais pas chez les femelles. Cette observation nous a encouragés à initier cette étude sur les différences en fonction du genre utilisant les tests comportementaux en rapport avec les fonctions de l'hippocampe chez les souris déficientes pour le récepteur 5-HT1a.Testant nos souris avec des paradigmes associés à l'anxiété, nous avons reproduit les données originales montrant que les souris transgéniques mâles ont un phénotype plus sévère que les souris mâles sauvages, mais qu'aucune différence n'est observée entre les femelles sauvages et transgéniques. De même, les souris mâles déficientes pour le récepteur 5-HT1a sont handicapées dans les tests de conditionnement au stress avec des stimuli aversifs. Nous faisons l'hypothèse que l'augmentation de la complexité de l'arborisation dendritique et l'augmentation de la force du signal synaptique entres les régions CA3 et CA1 de l'hippocampe dans le stratum radiatum perturbe la propagation du signal nerveux qui conduit à l'hyperactivation des neurones du secteur CA1. Ceci conduit à une mémoire de stress altérée chez les souris mâles déficientes pour le récepteur 5-HT1a. Un mécanisme similaire dans l'hippocampe ventral contribue probablement aux différences en fonction du genre dans les tests pour le comportement de type anxieux qui ont été rapportés dans les études originales de 1998. Les mesures de protéine et de mRNA ont mis en évidence une augmentation de l'expression du récepteur NMDA contenant la sous- unité NR2B dans les souris déficientes pour le récepteur 5-HT1a à P15. Dans les cultures organotypiques d'hippocampe, nous avons commencé à disséquer les messagers secondaires à l'activation du récepteur 5-HT1a qui sont impliqués dans la régulation de la croissance dendritique des neurones pyramidaux pendant la période postnatale précoce. Nous avons démontré que les récepteurs NR2B sont en aval de l'activation du récepteur 5-HT1a et qu'ils sont impliqués dans l'accroissement du nombre de dendrites chez la souris mâle déficiente pour le récepteur 5-HT1a. Bien que la cascade de signalisation du récepteur 5-HT1a pour réguler les récepteurs NMDA contenant le NR2B ne soit pas établie, CaMKII est identifié comme un effecteur potentiel pour altérer le transport du récepteur NMDA à la synapse. D'autre part, Erk1/2 est probablement un messager en aval du NR2B du récepteur NMDA, et a été documenté comme suffisant pour réguler l'arborisation dendritique. L'augmentation de NR2B à la synapse des souris déficientes pour le récepteur 5-HT1a peut conduire à une augmentation de l'excitotoxicité dans les cellules. Nous avons observé une augmentation chez la souris déficiente pour le récepteur 5-HT1a de la mort cellulaire dans des tranches d'hippocampe stimulées, ce qui peut être en relation avec la réduction de la survie des neurones générés dans l'hippocampe de la souris mâle transgénique adulte par rapport à la souris mâle sauvage. De plus, la convergence de la signalisation du récepteur 5-HT1a sur la signalisation de la sous-unité NR2B du récepteur NMDA permet à l'oestrogène d'interférer avec sa voie de signalisation du récepteur de l'oestrogène couplé à une protéine G (GPER-1), ceci permettant à l'oestrogène de réduire la taille de l'arborisation des neurones pyramidaux de CA1 chez la femelle de la souris déficiente pour le récepteur 5-HT1a. En conclusion, nos observations suggèrent fortement qu'un mécanisme hormonal convergeant sur la voie de signalisation de la sous-unité NR2B du récepteur NMDA permet la normalisation de l'exubérance des dendrites des neurones CA1 de l'hippocampe et du comportement des souris femelles déficientes pour le récepteur 5-HT1a. Ceci donne une explication possible pour la différence en fonction du genre dans l'apparition de troubles mentaux avec les variations du récepteur 5-HT1a comme facteur de prédisposition important

Synaptic Adhesion Molecules Regulate the Integration of New Granule Neurons in the Postnatal Mouse Hippocampus and their Impact on Spatial Memory.

Postnatal hippocampal neurogenesis induces network remodeling and may participate to mechanisms of learning. In turn, the maturation and survival of newborn neurons is regulated by their activity. Here, we tested the effect of a cell-autonomous overexpression of synaptic adhesion molecules on the maturation and survival of neurons born postnatally and on hippocampal-dependent memory performances. Families of adhesion molecules are known to induce pre- and post-synaptic assembly. Using viral targeting, we overexpressed three different synaptic adhesion molecules, SynCAM1, Neuroligin-1B and Neuroligin-2A in newborn neurons in the dentate gyrus of 7- to 9-week-old mice. We found that SynCAM1 increased the morphological maturation of dendritic spines and mossy fiber terminals while Neuroligin-1B increased spine density. In contrast, Neuroligin-2A increased both spine density and size as well as GABAergic innervation and resulted in a drastic increase of neuronal survival. Surprisingly, despite increased neurogenesis, mice overexpressing Neuroligin-2A in new neurons showed decreased memory performances in a Morris water maze task. These results indicate that the cell-autonomous overexpression of synaptic adhesion molecules can enhance different aspects of synapse formation on new neurons and increase their survival. Furthermore, they suggest that the mechanisms by which new neurons integrate in the postnatal hippocampus conditions their functional implication in learning and memory

Multi-method study of the Middle Pleistocene loess–palaeosol sequence of Köndringen, SW Germany

Loess–palaeosol sequences (LPSs) remain poorly investigated in the southern part of the Upper Rhine Graben but represent an important element to understand the environmental context controlling sediment dynamics in the area. A multi-method approach applied to the LPS at Köndringen reveals that its formation occurred during several glacial–interglacial cycles. Field observations, as well as colour, grain size, magnetic susceptibility, organic carbon, and carbonate content measured in three profiles at 5 cm resolution, provide detailed stratigraphical information. Only minor parts of the LPS are made up of loess sediment, whereas the major parts are polygenetic palaeosols and pedosediments of varying development that are partly intersected, testifying to a complex local geomorphic evolution. The geochronological framework is based on 10 cm resolution infrared-stimulated luminescence (IRSL) screening combined with 18 multi-elevated-temperature post-IR IRSL ages. The luminescence ages indicate that two polygenetic, truncated Luvisols formed during marine isotope stages (MISs) 9(–7?) and MIS 5e, whereas unaltered loess units correspond to the last glacial (MISs 5d–2) and MIS 8. The channel-like structure containing the two truncated Luvisols cuts into &gt; 2 m thick pedosediments apparently deposited during MIS 12. At the bottom of the LPS, a horizon with massive carbonate concretions (loess dolls) occurs, which may correspond to at least one older interglacial.</p

Evidence for Bronze Age and Medieval tin placer mining in the Erzgebirge mountains, Saxony (Germany)

Abstract Tin is an essential raw material both for the copper–tin alloys developed during the Early Bronze Age and for the casting of tableware in the Medieval period. Secondary geological deposits in the form of placers (cassiterite) provide easily accessible sources but have often been reworked several times during land-use history. In fact, evidence for the earliest phase of tin mining during the Bronze Age has not yet been confirmed for any area in Europe, stimulating an ongoing debate on this issue. For this study, a broad range of methods (sedimentology, pedology, palynology, anthracology, OSL/14C-dating, and micromorphology) was applied both within the extraction zone of placer mining and the downstream alluvial sediments at Schellerhau site in the upper eastern Erzgebirge (Germany). The results indicate that the earliest local removal of topsoil and processing of cassiterite-bearing weathered granite occurred already in the early second millennium BC, thus coinciding with the early and middle Bronze Age period. Placer mining resumed in this area during the Medieval period, probably as early as the 13th century AD. A peak of alluvial sedimentation during the mid-15th century AD is probably related to the acquisition of this region by the Elector of Saxony and the subsequent promotion of mining

Colluvial sediments originating from past land-use activities in the Erzgebirge Mountains, Central Europe: occurrence, properties, and historic environmental implications

Colluvial sediments originating from soil erosion on slopes have proven to constitute significant evidence for tracing past human impact on mountain landscapes. In the Central European Erzgebirge (Ore) Mountains, colluvial sediments are associated with specific landforms (footslopes, slope flattenings, dells) and cover a share of 11% (11,905 ha) of the regional soil landscape. Thirteen pedosedimentary sections with colluvial layers were investigated at five forested sites (520–730 m a.s.l.) within a context of mining archaeology, integrating data from pedology, archaeology, palaeobotany, and geochronology. The thickness of the gravel-bearing loamy, silty, and sandy colluvial layers is up to 70 cm, which are mostly located on top of the sections. The geochronological ages and archaeological data reveal a high to late medieval to post-medieval age of the colluvial sediments. Pollen data show a drastic decline of the mountain forests in the late twelfth to fifteenth centuries AD accompanied by an increase of pioneer trees and spruce at the expense of fir and beech. The primary cause of soil erosion and subsequent colluvial deposition at the sites investigated is medieval to post-medieval mining and other early industrial activities. A compilation of 395 radiocarbon and OSL ages, obtained from colluvial sediments at 197 upland sites in Central Europe, shows that anthropogenically initiated colluvial dynamics go as far back as the late Bronze Age to the early Iron Age. Most ages derive from the medieval to post-medieval period, corresponding to the general intensification of settlement and land-use activities including deforestation and widespread ore mining