ASD

Question 1

What is ASD characterised by

Answer 1

Impaired social interaction, communication deficits, stereotyped repetitive behaviour.

Question 2

What is the prevalence of ASD

Answer 2

1/68, 4:1 in males

Question 3

What are the life long challengnes of ASD?

Answer 3

Socio and economic burden, social interaction (anxiety, coping mechanisms may be adapted), restricted access to education,, no cure.

Question 4

Describe the ASD triangle

Answer 4

Communication, repetitive/restricted behaviours, social interaction.

Question 5

What are the comorbidities of ASD

Answer 5

Gi symptoms, sleep, seizures, aggression, motor disorders, anxiety, sensory deficits- think fussiness with food. Often have hypotnia (low muscle tone)

Question 6

Discuss motor disorders in relation to ASD

Answer 6

All have repetitive behaviours, 60-80% will have hypotonia, gait problems, toe walking and apraxia. Both gross and fine motor impairments are common (simple grip force, handwriting, gait)- The cause of the movement disorders and repetitive behaviour is not known.

Question 7

What are some of the brain regions involved in the movement disorders

Answer 7

Dorsal striatum (C and P), ventral striatum (NA- reward pathway and OT), GP,VP,SN, subthalmic nucleus. These are also involved in Tourette syndrome, OCD and PD. We known that all voluntary movement involves motor neurons in the SC and brainstem that cuase the contraction of skeletal muscles. The stratium and cerebellum modify these inputs.

Question 8

Medium spinal neurons

Answer 8

Main gabanergic projections in the neurons of the stratium project out to other regions in the striatum. These are based on dopamine receptors (D1 and D2)

Question 9

Give a brief discussion of genetics

Answer 9

Identical twin with a sibling you are 60-90% non identical 20%, more than 100 genes invovled, associated with synaptic mutations.

Question 10

Genes that are mutated in Autism are related to synaptic function what are their roles

Answer 10

Vesicle release, synaptic scaffolding, receptor proteins, PSD (integrate signals)

Question 11

Why use mice?

Answer 11

Breed genetically identical or induce mutation.

House in environments that are identical.

Question 12

Discuss model validity in terms of construct, face, predictive.

Answer 12

Construct- similar aetiology (eg gene mutation)- the way in which you made the model makes sense in terms of the disease.
Face validity- traits that come along with the disease.
Predictive validity- response to clinically effective treatments.

Question 13

Mouse models

Answer 13

30 models, including transgenic, phenotype first (weird mouse –test) and environmental models (toxins, valporate)

Question 14

In the mutation of NLGN3 R451C what percentage of protein reaches the membrane?

Answer 14

10%

Question 15

What does mutations of NL3 do in mice?

Answer 15

Social: Increase aggression (reversed by resperidone), communication- reduced vocalisation in early development.
Repetitivie- knock out and missense show improvements in motor learning- in autism you get highly agile children- repetitive behaviour keep learning.

Question 16

What did the rotarod assay show?

Answer 16

It showed by 7th trial KO did better (with increasing speed)

Question 17

How do we answer which brain areas at better for mice at the rotarod?

Answer 17

• Transgenic mice (mice bred with genes deleted or mutated)- eg NL3-KO
• Conditional mutants (genes deleted or mutated in specific brain regions- or at a specific stage in development)
• Viral construct (inject virus so that the gen mutation is expressed in a small area of the brain)• Anaesthesised the mouse put it in a grid and get the mouse brain axis and get coordinates and inject into the area. The expression is linked to GFP see all the ells with the virus deletes the gene they want to deleted.All cells with the virus you can see where they are

Question 18

What did the conditional mutants show?

Answer 18

Through the use of specific promotors you could delete regions in the brain. Taking the D1 Cre mouse to only cells that are expressing the D1 receptor.. When NL# is deleted from neurons in the stratium motor learning is increased. This experiement showed the dorsal straitum and the nucleus accumbens.

Question 19

What did the viral construct experiments demonstrate

Answer 19

Through the injection of a viral construct targeting all neurons, only green flourescent neurons at the injection site have NL3 deleted. You can get into specific areas. This showed that deleting NL3 in DS no change, deleting NL3 in NAC enhances motor neurons.

Question 20

What was the overall conclusion in this experiment

Answer 20

D1 spiny neurons in the NA are altered in NL3 mice.

Question 21

What are some strategies to understand other autism endophenotypes

Answer 21

• Compare mice using a simple assay
o In this case the rotarod test (increase the speed and time how long for the mouse to fall off)Simple assay and motor experiment in the lab
o Other tests for different endophenotypes- might use an aggressive test
o Video of grooming, aggression test etc
o Generate mice with different patterns of gene expression and compare using the original assay.
• Transgenic, conditional mutants, viral injections
• But note that these experiments are very expensive and time consuming.