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DMSO has a widespread use as a vehicle for water-insoluble therapeutic drug candidates but may also exert disease-relevant pharmacological effects by itself. However, its influence on the CNS has hardly been addressed. Here we examined the brain structure and function following chronic exposure to low DMSO dose at a paradigm with flawed synaptic connectivity in a preclinical transgenic mouse model for Alzheimer's disease (APPSDL mice). DMSO treatment increased spine density in a region-specific manner in the hippocampus of APPSDL mice ex vivo and in vivo. Moreover, DMSO exhibited clear influence on the behavior of this mouse line by enhancing hippocampal-dependent spatial memory accuracy, modulating hippocampal-independent olfactory habituation and displaying anxiolytic effect. Despite that most of the action of DMSO was observed in animals with elevated Aβ levels, the drug did not exert its function via decreasing the oligomeric Aβ species. However, challenging organotypic hippocampal slice cultures with NMDA receptor antagonist MK-801 recapitulated the effect of DMSO on spine density, indicating a tuning influence of DMSO on receptor signalization. Our findings demonstrate that DMSO should be considered as a true bioactive compound, which has the potential to be a beneficial adjuvant to counteract Aβ-mediated synaptotoxicity and behavioral impairment.

Low expression of the human serotonin transporter (5-HTT) gene presumably interacts with stressful life events enhancing susceptibility for affective disorders. 5-Htt knockout (KO) mice display an anxious phenotype, and behavioural differences compared to wild-type (WT) mice are exacerbated after repeated loser experience in a resident-intruder stress paradigm. To assess whether genotype-dependent and stress-induced behavioural differences are reflected in alterations of neuronal morphology in limbic areas, we studied dendritic length and complexity of pyramidal neurons in the anterior cingulate and infralimbic cortices (CG, IL), hippocampus CA1 region, and of pyramidal neurons and interneurons in the lateral (La) and basolateral (BL) amygdaloid nuclei in Golgi–Cox-stained brains of male WT and 5-Htt KO control and loser mice. Spine density was analysed for IL apical and amygdaloid apical and basal pyramidal neuron dendrites. While group differences were absent for parameters analysed in CG, CA1 and amygdaloid interneurons, pyramidal neurons in the IL displayed tendencies to shorter and less spinous distal apical dendrites in 5-Htt KO controls, and to extended proximal dendrites in WT losers compared to WT controls. In contrast, spine density of several dendritic compartments of amygdaloid pyramids was significantly higher in 5-Htt KO mice compared to WT controls. While a tendency to increased spine density was observed in the same dendritic compartments in WT after stress, changes were lacking in stressed compared to control 5-Htt KO mice. Our findings indicate that disturbed 5-HT homeostasis results in alterations of limbic neuronal morphology, especially in higher spinogenesis in amygdaloid pyramidal neurons. Social stress leads to similar but less pronounced changes in the WT, and neuroplasticity upon stress is reduced in 5-Htt KO mice.

The role of hyperphosphorylation of tau in Alzheimer's disease is still unsolved. Here we describe a novel transgenic mouse model, expressing a pseudohyperphosphorylated (PHP) variant of the longest human CNS tau isoform in forebrain neurons. We report that pseudohyperphosphorylation decreases phosphorylation at T205 while other sites (T212, S262) are less or not affected compared to mice expressing wildtype tau. Despite the differences in phosphorylation, the subcellular distribution of tau is not affected and mice do not develop highly aggregated states of tau. PHP tau expressing mice do not show any evidence for neurodegeneration as determined from morphometric measurements of neocortical regions, caspase activation, analysis of mitochondrial dysfunction, or determination of spine densities. In agreement, no differences in learning and memory are observed. The data indicates that moderate levels of modified tau alone are not sufficient to induce tau aggregation or neurodegeneration in transgenic mice. With our model it becomes possible to study the effects of hyperphosphorylation at conditions which may prevail in an early preaggregation state of the disease.

Humans differing in the amount of serotonin transporter (5-HTT) are known to be differentially prone to neuropsychiatric disorders. Genetically modified mice eliciting abrogated transporter function display a number of corresponding phenotypic changes in behavioural tests. However, a characterisation of the effects of serotonergic malfunction on the day-to-day life is still missing. Yet, this is precisely what an animal model is needed for in order to be meaningful for translation into human anxiety disorders. Homozygous 5-HTT knockout mice, heterozygous 5-HTT mice, and wild-type controls were housed in groups of males of the same genotype in spacious and richly structured cages. This enriched environment allowed the animals to show a wide variety of spontaneous behavioural patterns quantified by a trained experimenter. Additionally the mice could emigrate from the cages through a tunnel and a water basin. The results revealed unaltered daily behaviour in heterozygous mice. In knockouts, however, reduced locomotion, increased socio-positive behaviour, and reduced aggressive behaviour were observed. Nevertheless, all groups showed a significant amount of aggressive behaviour and there were no differences regarding the establishment of dominance relationships, emigration, and the number of animals remaining in their groups. In a second step, pairs of heterozygous and wild-type males and pairs of knockout and wild-type males were brought together in order to assess their ability to obtain a dominant social position in a direct encounter. Heterozygous mice did not differ from wild-type mice but knockout mice were significantly inferior in obtaining the dominant position. In addition to confirming multiple effects of abolished 5-HTT function in a real life situation, this study supports the central role of the 5-HTT in the control of social interactions. © 2010 Elsevier B.V. All rights reserved.

The behaviour of transgenic animals modelling human diseases such as Alzheimer's disease (AD) is typically characterised in artificial apparatuses rather than labour-intensively observing their spontaneous behaviour in the home environment. Here we report on an in-depth behavioural characterisation of the day-to-day life of a murine model for AD living in a large (6.6 m 2 ) semi-naturalistic indoor enclosure. In a genotype-blind investigation, 40 different behavioural patterns of wildtype and transgenic animals were recorded at early ages, before plaques can be found in the brains of the transgenic mice; and later in life, when these mice are known to exhibit AD-like plaques. Basal stress hormone levels (corticosterone) and cerebral amyloid-β depositions were determined, and compared with individually and group-housed mice from non-enriched standard cages. Semi-naturalistically housed transgenics could not be differentiated from wildtypes by their behavioural profiles nor by basal levels of corticosterone. Surprisingly, the brains of these transgenics revealed an even more pronounced plaque load than controls from standard-housing conditions. Behavioural traits are known to involve gene–environment interactions. Here we show for the first time that despite high β-amyloid plaque load the day-to-day life of AD mice is not compromised when the genetic predisposition interacts with a generous physically and socially enriched environment.

After we could recently demonstrate a beneficial effect of environmental enrichment on AD-like brain pathology in female TgCRND8 mice [Ambrée O, Leimer U, Herring A, Görtz N, Sachser N, Heneka MT, et al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 2006;169:544-52] the present study focuses on the behavioural effects of environmental enrichment with special emphasis on learning and memory performance in this AD model. In the first experiment spontaneous exploration, locomotor activity and anxiety-related behaviour were assessed as the performance in learning tasks can be biased substantially by exploratory behavioural traits. In the second experiment spatial memory in the Barnes maze test and object recognition memory were examined. Regarding exploratory behaviour transgenic mice from standard housing condition were statistically indistinguishable from wild-type controls. Enrichment had comparable effects in both genotypes indicated by higher levels of exploration and locomotor activity. In transgenic mice the elevated plus-maze revealed less anxiety-related behaviour due to enrichment in contrast to wild-type mice that statistically did not differ in anxiety-related behaviour. Concerning learning and memory performance, cognitive deficits of standard housed transgenic mice could be demonstrated in both learning tasks. Surprisingly, in both housing conditions a significantly higher number of transgenic mice refused to explore any objects compared to wild-type mice. Furthermore, the Barnes maze test revealed deficits of the transgenic mice in spatial memory compared to wild-type mice whereas no effect of environmental enrichment was detectable. Thus environmental enrichment increased exploratory behaviour and decreased anxiety-related behaviour but could not clearly ameliorate deficits in learning and memory performance of TgCRND8 mice.

Several studies on both humans and animals reveal benefits of physical exercise on brain function and health. A previous study on TgCRND8 mice, a transgenic model of Alzheimer's disease, reported beneficial effects of premorbid onset of long-term access to a running wheel on spatial learning and plaque deposition. Our study investigated the effects of access to a running wheel after the onset of Abeta pathology on behavioural, endocrinological, and neuropathological parameters. From day 80 of age, the time when Abeta deposition becomes apparent, TgCRND8 and wildtype mice were kept with or without running wheel. Home cage behaviour was analysed and cognitive abilities regarding object recognition memory and spatial learning in the Barnes maze were assessed. Our results show that, in comparison to Wt mice, Tg mice were characterised by impaired object recognition memory and spatial learning, increased glucocorticoid levels, hyperactivity in the home cage and high levels of stereotypic behaviour. Access to a running wheel had no effects on cognitive or neuropathological parameters, but reduced the amount of stereotypic behaviour in transgenics significantly. Furthermore, wheel-running was inversely correlated with stereotypic behaviour, suggesting that wheel-running may have stereotypic qualities. In addition, wheel-running positively correlated with plaque burden. Thus, in a phase when plaques are already present in the brain, it may be symptomatic of brain pathology, rather than protective. Whether or not access to a running wheel has beneficial effects on Alzheimer-like pathology and symptoms may therefore strongly depend on the exact time when the wheel is provided during development of the disease.

We report the generation and analysis of mutant mice bearing a targeted disruption of the heparan sulfate (HS)-modifying enzyme GlcNAc N-deacetylase/N-sulfotransferase 3 (NDST3). NDST3-/- mice develop normally, are fertile, and show only subtle hematological and behavioral abnormalities in agreement with only moderate HS undersulfation. Compound mutant mice made deficient in NDST2;NDST3 activities also develop normally, showing that both isoforms are not essential for development. In contrast, NDST1-/-;NDST3-/- compound mutant embryos display developmental defects caused by severe HS undersulfation, demonstrating NDST3 contribution to HS synthesis in the absence of NDST1. Moreover, analysis of HS composition in dissected NDST3 mutant adult brain revealed regional changes in HS sulfation, indicating restricted NDST3 activity on nascent HS in defined wild-type tissues. Taken together, we show that NDST3 function is not essential for development or adult homeostasis despite contributing to HS synthesis in a region-specific manner and that the loss of NDST3 function is compensated for by the other NDST isoforms to a varying degree.

BC1 RNA is a small non-messenger RNA common in dendritic microdomains of neurons in rodents. In order to investigate its possible role in learning and behaviour, we compared controls and knockout mice from three independent founder lines established from separate embryonic stem cells. Mutant mice were healthy with normal brain morphology and appeared to have no neurological deficits. A series of tests for exploration and spatial memory was carried out in three different laboratories. The tests were chosen as to ensure that different aspects of spatial memory and exploration could be separated and that possible effects of confounding variables could be minimised. Exploration was studied in a barrier test, in an open-field test, and in an elevated plus-maze test. Spatial memory was investigated in a Barnes maze and in a Morris water maze (memory for a single location), in a multiple T-maze and in a complex alley maze (route learning), and in a radial maze (working memory). In addition to these laboratory tasks, exploratory behaviour and spatial memory were assessed under semi-naturalistic conditions in a large outdoor pen. The combined results indicate that BC1 RNA-deficient animals show behavioural changes best interpreted in terms of reduced exploration and increased anxiety. In contrast, spatial memory was not affected. In the outdoor pen, the survival rates of BC1-depleted mice were lower than in controls. Thus, we conclude that the neuron-specific non-messenger BC1 RNA contributes to the aptive modulation of behaviour.