Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors

In humans, neuroligin-3 mutations are associated with autism, while in mice the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum, but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse, and thereby provide a plausible circuit substrate for autism pathophysiology

Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors

In humans, neuroligin-3 mutations are associated with autism, while in mice the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum, but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse, and thereby provide a plausible circuit substrate for autism pathophysiology

Culture, entrepreneurship and uneven development: a spatial analysis

Interest in the proposed connection between culture and entrepreneurship has grown significantly in recent years. However, less attention has been given to the nature of the overall impact of this proposed association on development outcomes, particularly at a local level. In response, this paper analyses the relationship between the nature of the culture, entrepreneurship and development experienced across localities, proposing that the link between culture and development is mediated by entrepreneurship. It focuses upon the concept of community culture, as well as embracing a notion of development incorporating both economic and social well-being outcomes. Drawing upon a multivariate spatial analysis of data from localities in Great Britain, the findings indicate that differences in rates of entrepreneurship are strongly influenced by the community culture present in these localities. Furthermore, a bidirectional relationship is found to exist between entrepreneurship and economic and social development outcomes. It is concluded that the embeddedness of local community culture presents a significant challenge for those places seeking to promote entrepreneurially-driven development

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits

Children’s participation in school grounds developments: creating a place for education that promotes children’s social inclusion

Abstract This paper advances the idea that &lsquo;education for the social inclusion of children&rsquo; is similar but different to &lsquo;inclusive education&rsquo; as it has come to be understood and used by some authors and UK government documents. &lsquo;Inclusive education&rsquo; tends to carry an inward emphasis on the participation of children in the education system (with discussions on school culture, transitions, truancy, exclusion rates, underachievement, and school leaving age). In contrast, education for the promotion of children&rsquo;s social inclusion requires an outward emphasis on children's participation in 'mainstream' society while they are still children. The latter emphasis is seen to be lacking in educational policy discourse in Scotland though a recent shift in policy towards education for active citizenship is noted. Examples are provided to show how many policy statements enact a limitation on the scope for education to promote children&rsquo;s social inclusion by emphasising children&rsquo;s deficits as social actors and focussing on the &lsquo;condition&rsquo; of social exclusion. The paper draws on an empirical study of children&rsquo;s participation in changing school grounds in Scotland. The analysis shows how the enclosure of learning in books, classrooms and normative curricula was challenged. Learning from school grounds developments was constructed relationally and spatially but the scope of what was to be learned was often delineated by adults. The paper closes with a discussion of how education that promotes the social inclusion of children will benefit from seeing both children and adults as current though partial citizens and utilising socio-spatial opportunities for the generation of uncertain curricula through their shared and/or differentiated participation

Shift in the Intrinsic Excitability of Medial Prefrontal Cortex Neurons following Training in Impulse Control and Cued-Responding Tasks

Impulse control is an executive process that allows animals to inhibit their actions until an appropriate time. Previously, we reported that learning a simple response inhibition task increases AMPA currents at excitatory synapses in the prelimbic region of the medial prefrontal cortex (mPFC). Here, we examined whether modifications to intrinsic excitability occurred alongside the synaptic changes. To that end, we trained rats to obtain a food reward in a response inhibition task by withhold responding on a lever until they were signaled to respond. We then measured excitability, using whole-cell patch clamp recordings in brain slices, by quantifying action potentials generated by the injection of depolarizing current steps. Training in this task depressed the excitability of layer V pyramidal neurons of the prelimbic, but not infralimbic, region of the mPFC relative to behavioral controls. This decrease in maximum spiking frequency was significantly correlated with performance on the final session of the task. This change in intrinsic excitability may represent a homeostatic mechanism counterbalancing increased excitatory synaptic inputs onto those neurons in trained rats. Interestingly, subjects trained with a cue that predicted imminent reward availability had increased excitability in infralimbic, but not the prelimbic, pyramidal neurons. This dissociation suggests that both prelimbic and infralimbic neurons are involved in directing action, but specialized for different types of information, inhibitory or anticipatory, respectively

Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS - Neurofilament as a Surrogate of Disease Progression

This work was supported by National MS Society (USA) under the Promise 2010 initiative and the MS Society of Great Britain and Northern Ireland as part of exploratory analysis for the UK MS Clinical Trial Network. VL is supported by Italian Minister of Health grant for young researcher 2008

Advances in multiple sclerosis research in 2009

The following review summarizes the progress in multiple sclerosis research published in the Journal of Neurology in 2009

Moving prison health promotion along: Towards an integrative framework for action to develop health promotion and tackle the social determinants of health

The majority of prisoners are drawn from deprived circumstances with a range of health and social needs. The current focus within ‘prison health’ does not, and cannot, given its predominant medical model, adequately address the current health and well-being needs of offenders. Adopting a social model of health is more likely to address the wide range of health issues faced by offenders and thus lead to better rehabilitation outcomes. At the same time, broader action at governmental level is required to address the social determinants of health (poverty, unemployment and educational attainment) that marginalise populations and increase the likelihood of criminal activities. Within prison, there is more that can be done to promote prisoners’ health if a move away from a solely curative, medical model is facilitated, towards a preventive perspective designed to promote positive health. Here, we use the Ottawa Charter for health promotion to frame public health and health promotion within prisons and to set out a challenging agenda that would make health a priority for everyone, not just ‘health’ staff, within the prison setting. A series of outcomes under each of the five action areas of the Charter offers a plan of action, showing how each can improve health. We also go further than the Ottawa Charter, to comment on how the values of emancipatory health promotion need to permeate prison health discourse, along with the concept of salutogenesis