Sala - Pharmacologic rescue of impaired cognitive flexability, social deficits, increased neurobehavioral model of autism. Flashcards
How valid is the oxt -/- mouse as a model for ASD?
It has been established that OT modulates social behaviors and social memory, and that ASD is a disorder characterized by deficits in these two areas.
Researchers use oxtr -/- mice (in which OT receptors are defective or absent, thus interupting social behavior) to act as a model for human ASP social deficits.
The working hypothesis is that if we can find a drug therapy to restore social behaviors in mice then we may translate this therapy in humans.
Ring colcudes that the oxt -/- mouse has face validity. Waht is evidence for this conclusion?
Oxtr -/- mice show an increased susceptibility to seizures. While this isn’t a core diagnostic criterion for ASD, there is high prevalence of seizures in ASD patients, and is a source of significant morbidity in ASD subjects
Although Ring concludes that the oxtr-/- mouse has face validity, he’s not as sure about its construct validity. What is construct validity, and why does he question this in the case of the oxtr-/- mouse?
Construct validity: refers to how well a tool (the oxtr -/- mouse) measures the construct that it is designed to measure
the findings still require further replication in larger populations to establish a level of confidence in oxtr as a risk gene for ASD
this makes the oxtr/ mouse have construct validity
Ring points out that the experiments of Sala et al. used only adult mice. Why does he consider this an important limitation of the study?
this relates to the question of construct validity.
if researchers are only using adult mice, they are really only testing mice that are oxytocin deficient and score low on measures of social interaction
if you only study adult mice, one cannot observe the emergence of ASD symptoms and see if the mouse is truly affected by a disorder analogous to ASD.
testing adult mice only means that one cannot study the efficacy of early treatment in these mice.
important to evaluate the treatment at earlier points (different ages) to evaluate whether a particular mechanism of action can deliver lasting changes in behavior phenotypes, suggesting the potential for disease modifcation
List the behavioural abnormalities seen in the oxtr-/- mouse
the behavioral phenotype of the oxt /-/ mouse includes
male-male aggression
reduced cognitive flexibility
susceptible to seizure
deficits in social interaction with other mice
The behavioural phenotype of the oxtr-/- mouse was described 10 years ago by a different group of researchers (Takayanagi et al., 2005). What new findings are described by Sala et al. that further characterize the phenotype?
The Takayanagi article described impaired behavior and increased aggression in the oxtr -/- mouse.
this phenotype was further characterized by Sala et al. when they showed these phenotypes again in their sample of oxtr -/- mice, plus they investigated the effects of one oxytocin and three aVP receptors on thee behaviors
found that selective antagonist for V1a (and AVP receptor) reduced the effect of OT administration in the oxtr -/- mice, and as well found that the density of V1a receptors in the CNS in these mice may underlie a compoensatory increase in sensitivity to oxytocin.
How old were the mice when pharmacological and behavioural tests were conducted?
6-11 weeks
How were sociability and social preference measured?
looking at reversal learning in a T-maze of Otrx -/- mice compared to wild-type control mice
How was aggression measured?
using exposure to male mouse
How was cognitive flexibility measured?
looking at reversal learning in a T-maze of Otrx -/- mice compared to wild-type control mice
How were seizures induced?
seizures were PTZ (pentylenetetrazole)-induced myoclonic seizures
How was seizure activity measured?
seizure activity was measured by electroenecephalographic recordings
The authors concluded that there was a decreased ratio of GABAergic vs. total presynaptic contacts on hippocampal neurons in oxtr-/- as compared to oxtr+/+ mice. How did they measure this ratio?
cultures were immunostained with antibodies directed against vGAT and vGlut-1 transporters
Using confocal microscopy coupled to computer-assisted image analysis, they quantified the optical densities of vGAT- and vGlut-positive synapses
The results show that the ratio between vGAT-positive over total (vGAT vGlut-1) synapses was significantly decreased in Oxtr/ versus Oxtr/ cultures
the ratio between vGlut-positive over total (vGAT vGlut-1) synapses was significantly increased inOxtr/ vs.Oxtr/ cultures
These results suggest that the balance between excitatory and inhibitory inputs in Oxtr/ hippocampi is set at a higher level of excitation (or lower level of inhibition) if compared with Oxtr/ hippocampi.
The authors used autoradiography to measure OTR and V1aR binding in the brains of oxtr-/- and oxtr+/+ mice. How was this done? For example, what ligands did they use to bind to the two receptors? Was it done in vivo or in vitro? How did they report their results? That is, what units were shown on the y-axes of the graphs in Fig. 5?
Oxtr/mice in vitro cultured for 7 and 10 days were doubly immunostained for the GABA vesicular transporter (vGAT) and the glutamate vesicular transporter (vGlut-1)
Images evidence the lower staining of GABAergic synapses in Oxtr/ neuronal cultures compared with Oxtr/.
in vitro
What behaviours were improved following these injections?
treatment with both peptides improved the reversal learning in Oxtr/ mice compared with animals receiving vehicle
OT significantly reduced the sociability ofOxtr/ mice.
