Genetically modified animals as models of neurodevelopmental conditions: A review of systematic review reporting quality.

Using genetically modified animals to model neurodevelopmental conditions helps better our understanding of biology underlying these conditions. Animal research has unique characteristics not shared with clinical research, meaning systematic review methods must be adapted to this context. We aim to evaluate the quantity, characteristics, and reporting quality of systematic reviews which synthesise research using genetically modified animals to model neurodevelopmental conditions.

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology.

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency.

A comparison of basal and activity-dependent exon splicing in cortical-patterned neurons of human and mouse origin.

Rodent studies have shown that alternative splicing in neurons plays important roles in development and maturity, and is regulatable by signals such as electrical activity. However, rodent-human similarities are less well explored. We compared basal and activity-dependent exon splicing in cortical-patterned human ESC-derived neurons with that in cortical mouse ESC-derived neurons, primary mouse cortical neurons at two developmental stages, and mouse hippocampal neurons, focussing on conserved orthologous exons.

Delayed recruitment of activity-dependent bulk endocytosis in Fmr1 knockout neurons.

The presynapse performs an essential role in brain communication via the activity-dependent release of neurotransmitters. However, the sequence of events through which a presynapse acquires functionality is relatively poorly understood, which is surprising, since mutations in genes essential for its operation are heavily implicated in neurodevelopmental disorders. We addressed this gap in knowledge by determining the developmental trajectory of synaptic vesicle (SV) recycling pathways in primary cultures of rat hippocampal neurons.

Laboratory Automated Interrogation of Data: an interactive web application for visualization of multilevel data from biological experiments.

A key step in understanding the results of biological experiments is visualization of the data. Many laboratory experiments contain a range of measurements that exist within a hierarchy of interdependence. An automated and facile way to visualize and interrogate such multilevel data, across many experimental variables, would (i) lead to improved understanding of the results, (ii) help to avoid misleading interpretation of statistics and (iii) easily identify outliers and sources of batch and confounding effects.

Cerebellar contributions to fear-based emotional processing: relevance to understanding the neural circuits involved in autism.

Cerebellar networks have traditionally been linked to sensorimotor control. However, a large body of evidence suggests that cerebellar functions extend to non-motor realms, such as fear-based emotional processing and that these functions are supported by interactions with a wide range of brain structures. Research related to the cerebellar contributions to emotional processing has focussed primarily on the use of well-constrained conditioning paradigms in both human and non-human subjects.

Skin-infiltrating T cells display distinct inflammatory signatures in lichen planus, bullous pemphigoid and pemphigus vulgaris.

Introduction: We here thought to dissect the inflammatory signature in lesions of three skin disorders, which show a common adaptive immune response against autoantigens of the skin but are characterized by diverging clinical phenotypes. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are type-2-dependent, IgG autoantibody-driven blistering disorders of mucous membranes and skin, which target desmoglein (Dsg)3 and bullous pemphigoid (BP)180, respectively. In contrast, lichen planus (LP) is a common chronic inflammatory disease of the skin and mucous membranes with a pronounced dermal T cell infiltrate.

Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons.

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes.

Epilepsy-Related CDKL5 Deficiency Slows Synaptic Vesicle Endocytosis in Central Nerve Terminals.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe early-onset epileptic encephalopathy resulting mainly from mutations in the X-linked gene. To determine whether loss of presynaptic CDKL5 function contributes to CDD, we examined synaptic vesicle (SV) recycling in primary hippocampal neurons generated from knockout rat males. Using a genetically encoded reporter, we revealed that CDKL5 is selectively required for efficient SV endocytosis.

Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion.

Background: Autism spectrum condition or 'autism' is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research.

Abnormal brain state distribution and network connectivity in a rat model.

Mutations in the gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase-activating protein domains have been deleted ( ), we analysed the duration and occurrence of wake, non-rapid eye movement and rapid eye movement brain states during 6 h multi-electrode EEG recordings.

NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease.

The NMDA receptor is a Ca-permeant glutamate receptor which plays key roles in health and disease. Canonical NMDARs contain two GluN2 subunits, of which 2A and 2B are predominant in the forebrain. Moreover, the relative contribution of 2A vs.

Ca2+ imaging of self and other in medial prefrontal cortex during social dominance interactions in a tube test.

The study of social dominance interactions between animals offers a window onto the decision-making involved in establishing dominance hierarchies and an opportunity to examine changes in social behavior observed in certain neurogenetic disorders. Competitive social interactions, such as in the widely used tube test, reflect this decision-making. Previous studies have focused on the different patterns of behavior seen in the dominant and submissive animal, neural correlates of effortful behavior believed to mediate the outcome of such encounters, and interbrain correlations of neural activity.

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3 rat model of autism.

Background: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3.

Cross-species considerations in models of neurodevelopmental disorders.

Advances in genetic technologies have facilitated the development of new animal models of neurodevelopmental disorders (NDDs), enabling cross-species validation of disease-related phenotypes and exploration of species-specific behaviours. In a recent study, Berg et al. used a rat model of Angelman Syndrome (AS) to identify Ube3a-dependent social behaviours, highlighting potential cross-species convergence and divergence between rodent models.

FMRP Sustains Presynaptic Function via Control of Activity-Dependent Bulk Endocytosis.

Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity.

CDKL5 deficiency disorder: a pathophysiology of neural maintenance.

Critical periods are developmental time windows in which functional properties of the brain are particularly susceptible to the organism's experience. It was thought that therapeutic strategies for neurodevelopmental disorders (NDDs) required early life intervention for successful treatment, but previous studies in a mouse model of Rett syndrome indicated that this may not be the case, as some genetic disorders result from disruptions of neuromaintenance. In this issue of the JCI, Terzic et al.

Experiential modulation of social dominance in a SYNGAP1 rat model of Autism Spectrum Disorders.

Advances in the understanding of developmental brain disorders such as autism spectrum disorders (ASDs) are being achieved through human neurogenetics such as, for example, identifying de novo mutations in SYNGAP1 as one relatively common cause of ASD. A recently developed rat line lacking the calcium/lipid binding (C2) and GTPase activation protein (GAP) domain may further help uncover the neurobiological basis of deficits in children with ASD. This study focused on social dominance in the tube test using Syngap (rats heterozygous for the C2/GAP domain deletion) as alterations in social behaviour are a key facet of the human phenotype.

Correction of amygdalar dysfunction in a rat model of fragile X syndrome.

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS.