video-imaging-spatiotemporal-maps-to-analyze-gastrointestinal

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

The enteric nervous system (ENS) plays an important role in regulating gastrointestinal (GI) motility and can function independently of the central ...

The University of Melbourne

Environmental enrichment (EE) has been shown to induce beneficial effects in mouse models of autism spectrum disorder (ASD), as well as animal models of a variety of other neurological and psychiatric disorders. Investigation of the mechanisms responsible for these changes in animal models will facilitate translation of EE and associated therapies to patient cohorts. In the accompanying article, Woo and Leon demonstrate clinical benefits of sensorimotor enrichment in patients with ASD. We discuss the implications of these findings for future development of therapeutic approaches for ASD and other brain disorders.

Translating preclinical environmental enrichment studies for the treatment of autism and other brain disorders: comment on Woo and Leon (2013).

Autism spectrum disorder (ASD) patients commonly exhibit a variety of comorbid traits including seizures, anxiety, aggressive behavior, gastrointestinal problems, motor deficits, abnormal sensory processing, and sleep disturbances for which the cause is unknown. These features impact negatively on daily life and can exaggerate the effects of the core diagnostic traits (social communication deficits and repetitive behaviors). Studying endophenotypes relevant to both core and comorbid features of ASD in rodent models can provide insight into biological mechanisms underlying these disorders. Here we review the characterization of endophenotypes in a selection of environmental, genetic, and behavioral rodent models of ASD. In addition to exhibiting core ASD-like behaviors, each of these animal models display one or more endophenotypes relevant to comorbid features including altered sensory processing, seizure susceptibility, anxiety-like behavior, and disturbed motor functions, suggesting that these traits are indicators of altered biological pathways in ASD. However, the study of behaviors paralleling comorbid traits in animal models of ASD is an emerging field and further research is needed to assess altered gastrointestinal function, aggression, and disorders of sleep onset across models. Future studies should include investigation of these endophenotypes in order to advance our understanding of the etiology of this complex disorder.

Studying autism in rodent models: reconciling endophenotypes with comorbidities.

Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.

Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome.

Epilepsy is a common comorbidity in patients with Autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3(R451C) (NL3(R451C)) and wild type (WT) mice. It has previously been reported that NL3(R451C) mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippocampus and somatosensory cortex. PTZ administration induces absence-seizures at low dose, and generalised convulsive seizures at higher dose. Susceptibility to absence seizures was examined by analysing the frequency and duration of spike-and-wave discharge (SWD) events and accompanying motor seizure activity induced by subcutaneous administration of low dosage (20 or 30 mg/kg) PTZ. Susceptibility to generalised convulsive seizures was tested by measuring the response to high dosage (60 mg/kg) PTZ using a modified Racine scale. There was no change in the number of SWD events exhibited by NL3(R451C) compared to WT mice following administration of both 20 mg/kg PTZ (1.17 ± 0.31 compared to 16.0 ± 11.16 events/30 min, NL3(R451C) vs WT respectively) and 30 mg/kg PTZ (7.5 ± 6.54 compared with 27.8 ± 19.9 events/30 min, NL3(R451C) versus WT respectively). NL3(R451C) mice were seizure resistant to generalised convulsive seizures induced by high dose PTZ compared to WT littermates (median latency to first > 3 s duration clonic seizure; 14.5 min versus 7.25 min, 95% CI: 1.625-2.375, p = 0.0009, NL3(R451C) vs WT respectively). These results indicate that the R451C mutation in the Nlgn3 gene, associated with ASD in humans, confers resistance to induced seizures, suggesting dysfunction of PTZ-sensitive GABAergic signalling in this mouse model of ASD.

Reduced susceptibility to induced seizures in the Neuroligin-3(R451C) mouse model of Autism.

Rapid transmembrane flow of sodium ions produces the depolarising phase of action potentials (APs) in most excitable tissue through voltage-gated sodium channels (NaV). Macroscopic currents display rapid activation followed by fast inactivation (IF) within milliseconds. Slow inactivation (IS) has been subsequently observed in several preparations including neuronal tissues. IS serves important physiological functions but the kinetic properties are incompletely characterised, especially the operative time-scales. Here we characterise for an "intermediate inactivation (II)" process in rat hippocampal CA1 neurons with time constants of the order of 101-102 ms. The half-inactivation potential (V0.5) of steady-state inactivation curves were hyperpolarised by increasing conditioning pulse duration from 50 to 500 ms. II state transitions were observed after opening as well as subthreshold potentials. Entry into II after opening was relatively insensitive to membrane potential and recovery of II became more rapid at hyperpolarised potentials. Near resting membrane potential it is estimated that 40% of channels occupy this intermediate state. II recovery was considerably slower from closed inactivated states than from inactivated states reached through the open state. Removal of IF with cytoplasmic papaine revealed time constants of INa decay corresponding to II and IS with long depolarisations. Dynamic clamp revealed attenuation of trains of APs over the 10(2) ms timescale suggesting a functional role of II in repetitive firing accommodation. These experimental findings could be reproduced with a Markov state model. It is likely that II affects several important aspects of hippocampal neuron response, and may provide a drug target for sodium channel modulation.

Properties of an Intermediate-duration Inactivation Process of the Voltage-gated Sodium Conductance in Rat Hippocampal CA1 Neurons.

Aggression is common in patients with autism spectrum disorders (ASD) along with the core symptoms of impairments in social communication and repetitive behavior. Risperidone, an atypical antipsychotic, is widely used to treat aggression in ASD. In order to understand the neurobiological underpinnings of these challenging behaviors, a thorough characterisation of behavioral endophenotypes in animal models is required.

Elisa Hill-Yardin

Department of Physiology

The University of Melbourne

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

Elisa Hill-Yardin

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Physiology

The University of Melbourne

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

Department of Physiology