B2B W4T1

Question 1

What are the core symptoms of ASD as observed in mouse models?

Answer 1

• Social interaction deficits
• Communication deficits
• Repetitive and restricted behaviours

These behaviours are assessed using various behavioural methods in mouse models.

Question 2

ASD is found in approximately what percentage of the population?

Answer 2

1 percent

ASD is a heterogeneous developmental disorder with varying presentations and aetiologies.

Question 3

What are the three aspects of validity considered when assessing mouse models for ASD?

Answer 3

• Construct validity
• Face validity
• Predictive validity

These aspects help determine how well a mouse model represents human ASD.

Question 4

Define construct validity in the context of mouse models.

Answer 4

The model displays the same biological dysfunction that causes the human disease

This includes genetic mutations or anatomical features similar to those found in humans.

Question 5

What is a disadvantage of mouse models regarding construct validity?

Answer 5

• Brain development is more complex and takes longer in humans
• Certain brain regions are larger and more complex in humans

These differences can hinder the accurate modeling of human biological dysfunction.

Question 6

What is face validity?

Answer 6

The model shows strong analogies to the endophenotypes of the human syndrome

This is crucial for ensuring that the model exhibits behaviours similar to those seen in humans with ASD.

Question 7

What is a challenge in modeling ASD in mice regarding communication?

Answer 7

Mice rely on olfactory cues, while humans rely on visual cues

This difference affects the underlying neural circuitry involved in social communication.

Question 8

What is predictive validity?

Answer 8

The model demonstrates an analogous response to treatments that prevent or reverse symptoms in the human condition

This aspect is important for evaluating the effectiveness of potential treatments.

Question 9

Name an inbred mouse strain that shows typical ASD-like behaviours.

Answer 9

BTBR

This strain exhibits reduced reciprocal social interactions, low sociability, and increased repetitive self-grooming.

Question 10

In the three-chamber test, BTBR mice show no preference for which chamber?

Answer 10

The chamber with a stranger mouse

This indicates low sociability compared to normal mice.

Question 11

What anatomical abnormality is observed in BTBR mice?

Answer 11

Agenesis of the anterior corpus callosum

This loss of white matter fibers connects the two cerebral hemispheres.

Question 12

What is the role of CNTNAP2 in relation to ASD?

Answer 12

It plays a role in neuronglia interactions and neuronal migration during embryonic development

Mutations in CNTNAP2 are strongly associated with ASD.

Question 13

What does SHANK3 stand for?

Answer 13

SH3 and multiple ankyrin repeat domains 3 protein

It is important for synaptogenesis and dendritic spine maturation.

Question 14

What behaviour do Cntnap2 knockout mice exhibit?

Answer 14

• Fewer ultrasonic vocalisations to the mother
• Increased repetitive grooming behaviours
• No preference for social interaction in the three-chamber test

These behaviours indicate face validity as an ASD model.

Question 15

What drug was used to treat Cntnap2 knockout mice to reverse hyperactivity?

Answer 15

Risperidone

Treatment with this drug showed significant improvements in behaviour.

Question 16

What is the significance of restoring Shank3 expression in adult mice?

Answer 16

It can rescue repetitive grooming behaviours and social preference

This suggests considerable plasticity in the adult brain.

Question 17

What are the two key signalling pathways activated by mGluR5?

Answer 17

• ERK pathway
• mTOR pathway

These pathways are involved in protein translation and long-term depression.

Question 18

True or false: Mouse models of ASD fully recapitulate the genetic defects found in human patients.

Answer 18

FALSE

For example, Cntnap2 knockout mice lack both copies of the gene, while most patients only lack one.

Question 19

What is the role of mGluR5 in the context of Shank3 mutants?

Answer 19

mGluR5 function is disrupted

Under basal conditions, mGluR5 activity is increased, but receptor activation reduces the response compared to controls.

Question 20

What effect does the mGluR5 antagonist MPEP have on grooming behaviours?

Answer 20

Reduces grooming behaviours

In contrast, the allosteric modulator CDPPB, which activates the pathway, increases grooming.

Question 21

What is Fragile X syndrome caused by?

Answer 21

Mutation of the FMR1 gene

This X-linked disorder affects synaptic plasticity and protein translation.

Question 22

What happens to local protein translation in the absence of FMRP?

Answer 22

Increases local protein synthesis

Loss of FMRP leads to hypersensitivity to ERK signalling activation.

Question 23

What was the outcome of reducing mGluR5 gene dosage in Fragile X models?

Answer 23

Phenotypes were rescued

This suggests that uncontrolled mGluR5 activity contributes to Fragile X symptoms.

Question 24

What is the role of the Tsc2 gene in tuberous sclerosis?

Answer 24

Negative regulator of the mTOR pathway

Reduced Tsc2 activity leads to increased protein translation.

Question 25

What was found in the hippocampus of **Tsc2 mutant mice**?

Answer 25

Reduced protein synthesis ## Footnote This finding was unexpected and suggests complexity in the underlying mechanisms.

Question 26

What were the results of comparing **LTD** between Fmr1 and Tsc2 mutants?

Answer 26

Opposite phenotypes observed ## Footnote LTD was reduced in Tsc2 mutants but increased in Fmr1 mutants.

Question 27

What is the implication of the findings regarding treatments for different types of **ASD**?

Answer 27

Treatment for one type may be detrimental to another ## Footnote This highlights the need for mechanistic studies in mouse models.

Question 28

What do **exome sequencing studies** identify in relation to ASD?

Answer 28

High-confidence ASD risk genes ## Footnote These studies often focus on de novo gene-disrupting mutations.

Question 29

Name three genes with recurring mutations associated with **ASD**.

Answer 29

* CHD8 * ARID1B * SETD5 ## Footnote These genes encode chromatin remodelling factors involved in gene expression during brain development.

Question 30

What behaviour was observed in **Chd8 heterozygous mice**?

Answer 30

No ASD-like behaviours ## Footnote They showed no social deficits or increased grooming.

Question 31

What is the significance of **construct validity** in mouse models?

Answer 31

Indicates the model accurately represents the underlying biological concept ## Footnote Chd8 mutant mice show good construct validity but poor face validity.

Question 32

What environmental factors have been established as contributing to **ASD**?

Answer 32

* Exposure to valproic acid during gestation * Zinc deficiency * Maternal immune activation ## Footnote These factors interact with genetic risk factors to influence ASD development.

Question 33

What did the study by Choi et al. demonstrate regarding **maternal immune activation**?

Answer 33

Induced ASD-like behaviours in offspring ## Footnote Behaviours included increased USV and low sociability, which could be prevented by IL-17 blocking antibodies.

Question 34

What are the limitations of **mouse models** in studying ASD?

Answer 34

* Lack of face validity * Complexity of developmental mechanisms ## Footnote Other model systems like rats, primates, and human brain organoids may complement mouse studies.