Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse.

Mitochondrial dysfunction is strongly associated with autism spectrum disorder (ASD) and the Inner mitochondrial membrane protein 2-like (IMMP2L) gene is linked to autism inheritance. However, the biological basis of this linkage is unknown notwithstanding independent reports of oxidative stress in association with both IMMP2L and ASD. To better understand IMMP2L's association with behaviour, we developed the Immp2lKD knockout (KO) mouse model which is devoid of Immp2l peptidase activity. Immp2lKD -/- KO mice do not display any of the core behavioural symptoms of ASD, albeit homozygous Immp2lKD -/- KO mice do display increased auditory stimulus-driven instrumental behaviour and increased amphetamine-induced locomotion. Due to reports of increased ROS and oxidative stress phenotypes in an earlier truncated Immp2l mouse model resulting from an intragenic deletion within Immp2l, we tested whether high doses of the synthetic mitochondrial targeted antioxidant (MitoQ) could reverse or moderate the behavioural changes in Immp2lKD -/- KO mice. To our surprise, we observed that ROS levels were not increased but significantly lowered in our new Immp2lKD -/- KO mice and that these mice had no oxidative stress-associated phenotypes and were fully fertile with no age-related ataxia or neurodegeneration as ascertained using electron microscopy. Furthermore, the antioxidant MitoQ had no effect on the increased amphetamine-induced locomotion of these mice. Together, these findings indicate that the behavioural changes in Immp2lKD -/- KO mice are associated with an antioxidant-like phenotype with lowered and not increased levels of ROS and no oxidative stress-related phenotypes. This suggested that treatments with antioxidants are unlikely to be effective in treating behaviours directly resulting from the loss of Immp2l/IMMP2L activity, while any behavioural deficits that maybe associated with IMMP2L intragenic deletion-associated truncations have yet to be determined.

Patient safety and quality care for children with intellectual disability: An action research study.

Children with intellectual disability experience significant challenges in accessing and receiving high-quality healthcare leading to poorer health outcomes and negative patient experiences. Families of these children often report a need for healthcare staff to better understand, communicate, and collaborate for better care while staff acknowledge a lack of training. To address this, we utilised an action research framework with a pre- and post- survey to evaluate an integrated continuing professional development and quality improvement program combining strategies from education, behavioural psychology and quality improvement that was delivered in two departments within a tertiary children's Hospital in Metropolitan Sydney in 2019-2020. Parents reported noticeable changes in the clinical practice of staff, and staff acknowledged and attributed their shift in behaviour to raising awareness and discussions around necessary adaptations. The program demonstrates a novel method for knowledge translation to practice and systems improvements.

Where are they now? An autism follow-up study.

AIM: To explore the stability of diagnosis and the relationship between behavioural, adaptive and developmental skills in early to middle childhood in children with autism spectrum disorder (ASD). METHODS: Fifty-four children recruited to the study were diagnosed with ASD before 42 months. Outcomes at follow-up after a mean interval of 64 months were measured using the Autism Diagnostic Observation Schedule, Vineland-II adaptive scale and Wechsler Intelligence Scale for Children and parental survey data. Scores before school were compared with follow-up data through descriptive, correlational and multiple regression analyses. RESULTS: ASD was confirmed in all children at follow-up (mean age 10 years). Fifty-eight percent of children were enrolled in a supported educational class or school and 42% were taking a psychotropic medication. Adaptive function improved significantly in 19% of children. Developmental and adaptive behavioural scores before school correlated with cognitive, behaviour and adaptive assessments at follow-up. CONCLUSION: At follow-up, the diagnosis was confirmed in all children. The children showed gains in their adaptive skills but and many required ongoing educational and behavioural support. Early developmental and adaptive assessments reliably predicted later educational support needs, cognitive and adaptive function and are a useful component of a diagnostic assessment.

Cytotoxic T cells swarm by homotypic chemokine signalling.

Cytotoxic T lymphocytes (CTLs) are thought to arrive at target sites either via random search or following signals by other leukocytes. Here, we reveal independent emergent behaviour in CTL populations attacking tumour masses. Primary murine CTLs coordinate their migration in a process reminiscent of the swarming observed in neutrophils. CTLs engaging cognate targets accelerate the recruitment of distant T cells through long-range homotypic signalling, in part mediated via the diffusion of chemokines CCL3 and CCL4. Newly arriving CTLs augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. Activated effector human T cells and chimeric antigen receptor (CAR) T cells similarly employ intra-population signalling to drive rapid convergence. Thus, CTLs recognising a cognate target can induce a localised mass response by amplifying the direct recruitment of additional T cells independently of other leukocytes.

Immune cells known as cytotoxic T lymphocytes, or CTLs for short, move around the body searching for infected or damaged cells that may cause harm. Once these specialised killer cells identify a target, they launch an attack, removing the harmful cell from the body. CTLs can also recognise and eliminate cancer cells, and can be infused into cancer patients as a form of treatment called adoptive cell transfer immunotherapy. Unfortunately, this kind of treatment does not yet work well on solid tumours because the immune cells often do not infiltrate them sufficiently. It is thought that CTLs arrive at their targets either by randomly searching or by following chemicals secreted by other immune cells. However, the methods used to map the movement of these killer cells have made it difficult to determine how populations of CTLs coordinate their behaviour independently of other cells in the immune system. To overcome this barrier, Galeano Niño, Pageon, Tay et al. employed a three-dimensional model known as a tumouroid embedded in a matrix of proteins, which mimics the tissue environment of a real tumour in the laboratory. These models were used to track the movement of CTLs extracted from mice and humans, as well as human T cells engineered to recognise cancer cells. The experiments showed that when a CTL identifies a tumour cell, it releases chemical signals known as chemokines, which attract other CTLs and recruit them to the target site. Further experiments and computer simulations revealed that as the number of CTLs arriving at the target site increases, this amplifies the chemokine signal being secreted, resulting in more and more CTLs being attracted to the tumour. Other human T cells that had been engineered to recognize cancer cells were also found to employ this method of mass recruitment, and collectively 'swarm' towards targeted tumours. These findings shed new light on how CTLs work together to attack a target. It is possible that exploiting the mechanism used by CTLs could help improve the efficiency of tumour-targeting immunotherapies. However, further studies are needed to determine whether these findings can be applied to solid tumours in cancer patients.

Chronic Treatment with 50 mg/kg Cannabidiol Improves Cognition and Moderately Reduces Aß40 Levels in 12-Month-Old Male AßPPswe/PS1ΔE9 Transgenic Mice.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-ß (Aß) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics. The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the AßPPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology. Importantly, studies have indicated that CBD works in a dose-dependent manner. Thus, this study determined the chronic effects of 50 mg/kg CBD in male AßPPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot. Vehicle-treated male AßPPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble Aß40 levels in the hippocampus of AßPPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPARγ markers in the cortex. This study demonstrates that therapeutic-like effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in AßPPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble Aß40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation.

Behavioural effects of high fat diet in adult Nrg1 type III transgenic mice.

Some diets appear to have detrimental effects on schizophrenia symptoms. Neuregulin 1 (NRG1) is a risk gene for schizophrenia and a recently developed transgenic mouse model for Nrg1 type III demonstrates a schizophrenia-relevant phenotype. The current study evaluated the behavioural response of Nrg1 type III transgenic mice to a high fat diet (HFD) to determine the potential interactive impact of diets and genetic risk factors on disease symptoms. Male and female Nrg1 III and control littermates (N = 13-24) were exposed during adulthood to either HFD or standard chow diet (CHOW) for eight weeks before being tested in behavioural domains relevant to schizophrenia. Locomotion and exploration, anxiety, social behaviours (including social preference), sensorimotor gating (i.e. prepulse inhibition, PPI), associative learning, and anhedonia were assessed. HFD increased the body weight gain of mice, suppressed locomotion, exploration, and anxiety-related behaviours in a sex-dependent manner. HFD augmented the PPI response in male mice and decreased anhedonia in a sucrose preference test. Finally, HFD had a sex-dependent impact on fear-associated memory with HFD-induced cognitive impairments being most prominent in Nrg1 transgenic females. In conclusion, HFD and mutant Nrg1 III interactively impair particular cognitive domains in a sex-specific manner. Thus, our preclinical data suggest that genetic predisposition to the schizophrenia risk gene NRG1 may modulate detrimental behavioural effects of diets. This indicates the importance to research further the role of particular diets in the context of populations at risk to develop schizophrenia.

Behavioural effects of high fat diet exposure starting in late adolescence in neuregulin 1 transmembrane domain mutant mice.

A limited number of studies suggest that poor diet choices may impact on the mental state of schizophrenia patients. Our own work found that high fat diet (HFD) reversed social recognition memory deficits in female mice mutant for the schizophrenia risk gene neuregulin 1 (i.e. Nrg1 transmembrane domain: Nrg1 TM HET). Sex effects are common in schizophrenia and adolescence is a period of increased sensitivity to environmental risk factors. Thus, we investigated whether adolescent HFD exposure modulates schizophrenia-relevant behaviours of male and female Nrg1 TM HET mice. Male and female Nrg1 TM HET and their control littermates were exposed to either HFD or a standard chow diet from late adolescence onwards. After 8 weeks, adult mice were tested for locomotion and exploration, social behaviours, sensorimotor gating (i.e. prepulse inhibition), and fear-associated learning and memory. Nrg1 TM HET mice exhibited hyper-locomotion and an anxiolytic-like phenotype across sex and Nrg1 males tended to show deficient fear-associated memory. HFD increased body weight over time in all mice, an effect less pronounced in Nrg1 female mice. The moderately suppressive effect of HFD on females' exploration was less evident in Nrg1 mutants. Nrg1 TM HET female mice also displayed a less pronounced increase in HFD-induced cue freezing and HFD modulated the response to the cue in a complex genotype-dependent manner. In conclusion, HFD exposure starting in late adolescence has sex-specific effects on exploration and fear-associated memory, which was less pronounced in females mutant for Nrg1. This suggests that research into the role of diets in schizophrenia-relevant domains should consider genetic risk factors for the disease as schizophrenia risk genes such as Nrg1 may modulate dietary effects.

Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP-independent mechanism.

Fragile X Syndrome is a neurodevelopmental disorder which affects intellectual, social and physical development due to mutation of the Fragile X mental retardation 1 (FMR1) gene. The resultant loss of Fragile X mental retardation protein can be modelled by Fmr1 gene knockout (KO) in mice. The current study investigated the behavioural effects of cannabidiol (CBD; a non-psychoactive phytocannabinoid) in male Fmr1 KO mice as a preclinical model for therapeutic discovery. Vehicle or CBD (5 or 20 mg/kg body weight) was administered to adult Fmr1 KO and wild type-like (WT) mice before they were tested in behavioural tasks including: open field (OF), elevated plus maze (EPM), spontaneous alternation, social preference, and passive avoidance tasks. Fmr1 KO mice were hyperlocomotive and hyperexplorative and habituated more slowly to a novel environment compared to control animals. Furthermore, Fmr1 KO mice showed fewer anxiety-related behaviours across tests. Effects of CBD were subtle and limited to the EPM, where CBD decreased the anxiety response of all mice tested. Acute CBD had no impact on locomotion or anxiety-related parameters in the OF. Cognitive performance of Fmr1 KO mice was equivalent to controls and not affected by CBD treatment. Brain concentrations of CBD were equivalent between genotypes, but in animals sacrificed 90 min post-administration, decreased plasma CBD in Fmr1 KO mice compared to WT suggested more rapid clearance of CBD by transgenic animals. Overall, acute CBD at the doses chosen did not selectively normalize behavioural abnormalities in Fmr1 KO mice, but reduced anxiety-like behaviour in both Fmr1 KO and WT mice.

Long-term behavioural effects of maternal obesity in C57BL/6J mice.

Diet is increasingly being recognised as an important contributor to mental health. A diet high in sugar and polyunsaturated fatty acids can have negative consequences for disease symptoms and outcomes in schizophrenia patients. There is also evidence that particular diets can have beneficial, therapeutic-like properties for human brain disorders. Additionally, dietary choices of mothers have been found to affect cognitive domains and anxiety behaviour of offspring. Here we investigated the effects of maternal high fat diet (HFD) on a variety of behavioural domains in offspring and also consider behaviours, which are schizophrenia-relevant. Female C57BL/6 J mice were fed HFD (N = 13) or chow (N = 11) from 6 weeks prior to mating, during gestation and lactation. The male offspring of these mothers were weaned onto chow on PND24 and underwent testing for a range of behavioural outcomes starting at 38 weeks of age. Offspring of HFD mothers were significantly heavier compared to those of control mothers from weaning and throughout the duration of the experiment. Offspring of HFD mothers had significantly improved sensorimotor gating compared to offspring of control mothers but showed no altered behavioural response in tests for cognition, sociability, locomotion or exploration. Future investigations are required to assess which HFD-induced factors are responsible for the effects, e.g. altered maternal nursing behaviour, altered gestational physiology, or others warrants further investigation.

Behavioural characteristics of the Prader-Willi syndrome related biallelic Snord116 mouse model.

Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans and is associated with several behavioural phenotypes such as altered motoric function, reduced activity, and learning disabilities. It can include mood instability and, in some cases, psychotic episodes. Recently, the Snord116 gene has been associated with the development of PWS, however, it's contribution to the behavioural aspects of the disease are unknown. Here we show that male and female mice lacking Snord116 on both alleles exhibit normal motor behaviours and exploration but do display task-dependent alterations to locomotion and anxiety-related behaviours. Sociability is well developed in Snord116 deficient mice as are social recognition memory, spatial working memory, and fear-associated behaviours. No sex-specific effects were found. In conclusion, the biallelic Snord116 deficiency mouse model exhibits particular endophenotypes with some relevance to PWS, suggesting partial face validity for the syndrome.