The du2J mouse model of ataxia and absence epilepsy has deficient cannabinoid CB1 receptor-mediated signalling

Key point summary • Cerebellar ataxias are progressive debilitating diseases with no known treatment and are associated with defective motor function and, in particular, abnormalities to Purkinje cells. • Mutant mice with deficits in Ca2+ channel auxiliary α2δ-2 subunits are used as models of cerebellar ataxia. • Our data in the du2J mouse model shows an association between the ataxic phenotype exhibited by homozygous du2J/du2J mice and increased irregularity of Purkinje cell firing. • We show that both heterozygous +/du2J and homozygous du2J/du2J mice completely lack the strong presynaptic modulation of neuronal firing by cannabinoid CB1 receptors which is exhibited by litter-matched control mice. • These results show that the du2J ataxia model is associated with deficits in CB1 receptor signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity due to reduced α2δ-2 subunit expression. Knowledge of such deficits may help design therapeutic agents to combat ataxias. Abstract Cerebellar ataxias are a group of progressive, debilitating diseases often associated with abnormal Purkinje cell (PC) firing and/or degeneration. Many animal models of cerebellar ataxia display abnormalities in Ca2+ channel function. The ‘ducky’ du2J mouse model of ataxia and absence epilepsy represents a clean knock-out of the auxiliary Ca2+ channel subunit, α2δ-2, and has been associated with deficient Ca2+ channel function in the cerebellar cortex. Here, we investigate effects of du2J mutation on PC layer (PCL) and granule cell (GC) layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneurone-Purkinje cell(IN-PC) synapses. Increased neuronal firing irregularity was seen in the PCL and, to a less marked extent, in the GCL in du2J/du2J, but not +/du2J, mice; these data suggest that the ataxic phenotype is associated with lack of precision of PC firing, that may also impinge on GC activity and requires expression of two du2J alleles to manifest fully. du2J mutation had no clear effect on spontaneous inhibitory postsynaptic current (sIPSC) frequency at IN-PC synapses, but was associated with increased sIPSC amplitudes. du2J mutation ablated cannabinoid CB1 receptor (CB1R)-mediated modulation of spontaneous neuronal spike firing and CB1Rmediated presynaptic inhibition of synaptic transmission at IN-PC synapses in both +/du2J and du2J/du2J mutants; effects that occurred in the absence of changes in CB1R expression. These results demonstrate that the du2J ataxia model is associated with deficient CB1R signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity and the ataxic phenotype.

Linguistic interfaces and language acquisition in childhood: introduction to the special issue

Much contemporary L1 acquisition theory and empirical research are guided by the hypothesis that acquisition delays in children are often related to the integration of information across grammatical and other cognitive modules, such as syntax and discourse-pragmatics (see e.g., Grinstead, 2010). This special issue brings together cutting edge research from all relevant paradigms addressing interface issues in child language acquisition and provides a platform for the study of the interaction between different levels of linguistic knowledge. In this introduction, we present the reader with the tools needed to best understand the contributions of the individual studies and what they bring to bear on larger theoretical questions as a collective.

Longitudinal investigation of the role of temperament and stressful life events in childhood anxiety

The current study investigated the longitudinal relationships between BI, life events, and anxiety in a sample of 102 behaviourally inhibited (BI) and 100 uninhibited (BUI) children aged 3 to 4 years. Children’s parents completed questionnaires on BI, stressful life events, and anxiety symptoms, and were administered a diagnostic interview three times in a 5-year period. In line with our hypotheses, negative life events, and negative behaviour- dependent life events (i.e. life events that are related to the children’s own behaviours) in particular, and the impact of negative life events, were predictive of increases in subsequent anxiety symptoms, the likelihood of having an anxiety disorder, and increased number of anxiety diagnoses over the five year follow-up period. Experiencing more positive, behaviour-independent life events decreased the risk of being diagnosed with an anxiety disorder. Furthermore, differences were found in life events between BI and BUI children. That is, BI children experienced fewer positive and specifically positive behaviour-dependent life events, and the impact of these positive life events was also lower in BI children than in BUI children. However, BI did not interact with life events in the prediction of anxiety problems as hypothesized. Therefore, this study seems to indicate that BI and life events act as additive risk factors in the development of anxiety problems.

Informing early intervention: preschool predictors of anxiety disorders in middle childhood

Background: To inform early intervention practice, the present research examines how child anxiety, behavioural inhibition, maternal overinvolvement, maternal negativity, mother-child attachment and maternal anxiety, as assessed at age four, predict anxiety at age nine. Method: 202 children (102 behaviourally inhibited and 100 behaviourally uninhibited) aged 3–4 years were initially recruited and the predictors outlined above were assessed. Diagnostic assessments, using the Anxiety Disorders Interview Schedule, were then conducted five years later. Results: Behavioural inhibition, maternal anxiety, and maternal overinvolvement were significant predictors of clinical anxiety, even after controlling for baseline anxiety (p,.05). No significant effect of negativity or attachment security was found over and above baseline anxiety (p..1). Conclusions: Preschool children who show anxiety, are inhibited, have overinvolved mothers and mothers with anxiety disorders are at increased risk for anxiety in middle childhood. These factors can be used to identify suitable participants for early intervention and can be targeted within intervention programs.

A genome-wide association meta-analysis identifies new childhood obesity loci

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).

Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression

To date, anticonvulsant effects of the plant cannabinoid, cannabidivarin (CBDV), have been reported in several animal models of seizure. However, these behaviourally observed anticonvulsant effects have not been confirmed at the molecular level. To examine changes to epilepsy-related gene expression following chemical convulsant treatment and their subsequent control by phytocannabinoid administration, we behaviourally evaluated effects of CBDV (400 mg/kg, p.o.) on acute, pentylenetetra- zole (PTZ: 95 mg/kg, i.p.)-induced seizures, quantified expression levels of several epilepsy-related genes (Fos, Casp 3, Ccl3, Ccl4, Npy, Arc, Penk, Camk2a, Bdnf and Egr1) by qPCR using hippocampal, neocortical and prefrontal cortical tissue samples before examining correlations between expression changes and seizure severity. PTZ treatment alone produced generalised seizures (median: 5.00) and significantly increased expression of Fos, Egr1, Arc, Ccl4 and Bdnf. Consistent with previous findings, CBDV significantly decreased PTZ-induced seizure severity (median: 3.25) and increased latency to the first sign of seizure. Furthermore, there were correlations between reductions of seizure severity and mRNA expression of Fos, Egr1, Arc, Ccl4 and Bdnf in the majority of brain regions in the CBDV+PTZ treated group. When CBDV treated animals were grouped into CBDV responders (criterion: seizure severity ≤ 3.25) and non-responders (criterion: seizure severity >3.25), PTZ-induced increases of Fos, Egr1, Arc, Ccl4 and Bdnf expression were suppressed in CBDV re- sponders. These results provide the first molecular confirmation of behaviourally observed effects of the non-psychoactive, anticonvulsant cannabinoid, CBDV, upon chemically-induced seizures and serve to underscore its suitability for clinical development.

Emotional reasoning and anxiety sensitivity: associations with social anxiety disorder in childhood

Background Two specific cognitive constructs that have been implicated in the development and maintenance of anxiety symptoms are anxiety sensitivity and emotional reasoning, both of which relate to the experience and meaning of physical symptoms of arousal or anxiety. The interpretation of physical symptoms has been particularly implicated in theories of social anxiety disorder, where internal physical symptoms are hypothesized to influence the individual's appraisals of the self as a social object. Method The current study compared 75 children on measures of anxiety sensitivity and emotional reasoning: 25 with social anxiety disorder, 25 with other anxiety disorders, and 25 nonanxious children (aged 7–12 years). Results Children with social anxiety disorder reported higher levels of anxiety sensitivity and were more likely than both other groups to view ambiguous situations as anxiety provoking, whether physical information was present or not. There were no group differences in the extent to which physical information altered children's interpretation of hypothetical scenarios. Limitations This study is the first to investigate emotional reasoning in clinically anxious children and therefore replication is needed. In addition, those in both anxious groups commonly had comorbid conditions and, consequently, specific conclusions about social anxiety disorder need to be treated with caution. Conclusion The findings highlight cognitive characteristics that may be particularly pertinent in the context of social anxiety disorder in childhood and which may be potential targets for treatment. Furthermore, the findings suggest that strategies to modify these particular cognitive constructs may not be necessary in treatments of some other childhood anxiety disorders.

Missionary children: The French Holy Childhood Association in European context, 1843-c.1914

In the mid-nineteenth century, thousands of children in Europe and beyond were organized into battalions of fundraisers for overseas missions. By the end of the century these juvenile missionary organizations had become a global movement, generating millions of pounds in revenue each year. While the transnational nature of the children’s missions and publications has been well-documented by historians, the focus has tended to be on the connections that were established by encounters between the young western donors, missionaries overseas and the non-western ‘other’ constructed by their work. A full exploration of the European political, social and cultural concerns that produced the juvenile missionaries movement and the trans-European networks that sustained it are currently missing from historical accounts of the phenomenon. This article looks at the largest of these organizations, the Catholic mission for children, the French Holy Childhood Association (L’Œuvre de la sainte enfance), to understand how the principles this mission sought to impose abroad were above all an expression of anxieties at home about the role of religion in the family, childhood and in civil society as western polities were modernizing and secularizing in the nineteenth century.

Intensive approaches for childhood fears

This chapter reports on the implementation of a brief psychological intervention for the treatment of fears in childhood.

The development of time-based prospective memory in childhood: the role of working memory updating

This large-scale study examined the development of time-based prospective memory (PM) across childhood and the roles that working memory updating and time monitoring play in driving age effects in PM performance. One hundred and ninety-seven children aged 5 to 14 years completed a time-based PM task where working memory updating load was manipulated within individuals using a dual task design. Results revealed age-related increases in PM performance across childhood. Working memory updating load had a negative impact on PM performance and monitoring behavior in older children, but this effect was smaller in younger children. Moreover, the frequency as well as the pattern of time monitoring predicted children’s PM performance. Our interpretation of these results is that processes involved in children’s PM may show a qualitative shift over development from simple, nonstrategic monitoring behavior to more strategic monitoring based on internal temporal models that rely specifically on working memory updating resources. We discuss this interpretation with regard to possible trade-off effects in younger children as well as alternative accounts.

Are happy youth also satisfied adults? An analysis of the impact of childhood factors on adult life satisfaction

This paper aims to consider whether there is a link between youth happiness levels and adult life satisfaction. Our results are unequivocal that such a link exists both because demographic and socio-economic conditions are persistent over a lifetime and also because there is a persistence in personality effects. To test this link, we estimate a model of happiness for a sample of young people. This model provides us with a range of variables measuring socio-economic effects and personality effects amongst young people. These variables are then included in the adult life satisfaction model. The model is estimated using data from the British Household Panel Survey for 1994–2008. In addition to childhood happiness levels influencing adult life satisfaction significantly, we also find that the youthful personality trait for happiness has a larger effect on adult life satisfaction than demographic and socio-economic conditions.

Autonomic arousal in childhood anxiety disorders: associations with state anxiety and social anxiety disorder

Background Psychophysiological theories suggest that individuals with anxiety disorders may evidence inflexibility in their autonomic activity at rest and when responding to stressors. In addition, theories of social anxiety disorder, in particular, highlight the importance of physical symptoms. Research on autonomic activity in childhood (social) anxiety disorders, however, is scarce and has produced inconsistent findings, possibly because of methodological limitations. Method The present study aimed to account for limitations of previous studies and measured respiratory sinus arrhythmia (RSA) and heart rate (HR) using Actiheart heart rate monitors and software (Version 4) during rest and in response to a social and a non-social stressor in 60 anxious (30 socially anxious and 30 ‘other’ anxious), and 30 nonanxious sex-and age-matched 7–12 year olds. In addition, the effect of state anxiety during the tasks was explored. Results No group differences at rest or in response to stress were found. Importantly, however, with increases in state anxiety, all children, regardless of their anxiety diagnoses showed less autonomic responding (i.e., less change in HR and RSA from baseline in response to task) and took longer to recover once the stressor had passed. Limitations This study focused primarily on parasympathetic arousal and lacked measures of sympathetic arousal. Conclusion The findings suggest that childhood anxiety disorders may not be characterized by inflexible autonomic responding, and that previous findings to the contrary may have been the result of differences in subjective anxiety between anxious and nonanxious groups during the tasks, rather than a function of chronic autonomic dysregulation.

Shared cognition in childhood anxiety: interpretation bias in preschool children and their parents

Although interpretation bias has been associated with the development and/or maintenance of childhood anxiety, its origins remain unclear. The present study is the first to examine intergenerational transmission of this bias from parents to their preschool-aged children via the verbal information pathway. A community sample of fifty parent–child pairs was recruited. Parents completed measures of their own trait anxiety and interpretation bias, their child’s anxiety symptoms, and a written story-stem measure, to capture the way parents tell their children stories. Interpretation bias was assessed in preschool-aged children (aged between 2 years 7 months and 5 years 8 months) using an extended story-stem paradigm. Young children’s interpretation bias was not significantly associated with their own anxiety symptoms. Neither was there evidence for a significant association between parent and child interpretation bias. However, parents who reported they would tell their child one or more threatening story endings in the written story-stem task had significantly higher anxiety than those who did not include any threatening story endings. In turn, children whose parents did not include any threatening endings in their written stories had significantly lower threat interpretations on the child story-stem paradigm, compared to those with parents who included at least one threatening story ending. The results suggest that parental verbal information could play a role in the development of interpretation bias in young children.