ASD

Question 1

What is the aetiology of ASD?

Answer 1

Is heterogeneous therefore cannot pin down single, involves changes in: cell proliferation, neurogenesis, migration, laminar organisation, neurite outgrowth, synaptogenesis etc.

Question 2

How is the cell cycle altered in ASD?

Answer 2

Shortened G1 and S phase:
G1) growth phase
S) DNA synthesis phase

This means overall cell cycle is accelerated and leads to massive overproliferation of neurons = larger and denser brain.

Question 3

In ASD how are neurons altered in brain size and structure?

Answer 3

ASD: more neurons with fewer synaptic connections (less mature/developed). The neurons are more compact.

The more severe the ASD the more these brain changes can be seen (more dense, more synapses)

Question 4

What are hcASD genes?

Answer 4

high confidence ASD genes: recurrent and reported accross multiple independent samples.

They are not present in typical population.

Thought to be over 100

Courchesne et al., 2020

Question 5

How do hcASD genes support idea of ASD being a multi organ disorder?

Answer 5

Mouse models of hcASD genes (Chd8) show wide spread expression during organogenesis. Gut, thyroid, heart and eyes as well as cerebellum and neocortex.

Leads to: microbiome changes, arterial maldevelopment and whole body overgrowth.

Courchesne et al., 2020

Question 6

Give 2 examples of hcASD genes.

Answer 6

Chd8: allelic variants associated with ASD, regulation of transcription, proliferation facilitation and RNA synthesis regulation.

FMR1: encodes FMRP (fragile X) and impacts AMPAR and therefore synaptic plasticity. Pathways regulated are found to be dysfunctional in ASD patients and there is also comorbidity.

Question 7

Give evidence for or against ASD starting pre-natally.

Answer 7

FOR

94% of hcASD genes expressed in prenatal development.

Courchesne et al., 2020

Question 8

What are Epoch 1 genes in ASD?

Answer 8

Genes implicated in 1-3rd trimesters of pregnancy.

Generally regulatory and cortex building genes = cell proliferation, neurogenesis, migration.

Question 9

What are Epoch 2 genes in ASD?

Answer 9

Genes implicated in 3rd trimester and early postnatal life.

Generally regulatory and impact synaptogenesis, neurite growth etc.

Question 10

How is layered strucure of the cortex changed in ASD?

Answer 10

Cortical minicolumns are more tightly packed.
Reduced neuronal size (esp layer V).
Layer VI is output layer and not significantly diff in ASD

Question 11

What are Von Economo Neurons

Answer 11

Neurons only found in humans, gorillas, whales and elephants = highly social animals that can self recognise in a mirror.

Thought to have evolved to speed up communication around big brains and implicated in fast intuitive evaluation of complex social situations.

Found in frontal insula and ACC.

Question 12

Outline how VENs are changed in ASD

Answer 12

Overexpressed with higher ratio of VEN to pyramidal neurons ( Santos et al., 2011) in layer V of frontal insula in post mortem.
Thought to underlie heightened interoception (physical sensation in body such as hunger) that has been described clinically.

Also shown to be morphologically different: swollen somata, corkskrew dendrites as well as being surrounded by oligodendrocytes = abnormal functioning.

NB: also shown that VENs are both over and under expressed in ACC… this complicates things.

Question 13

Outline role of Neuroligins and neurexins

Answer 13

Synaptic cell adhesion molecules that work by binding to each other or intracellular proteins. Essential for neuronal function as in KO mice there are deficits in synaptic transmission.

Question 14

Outline neuroligin mutation in ASD

Answer 14

NLgn3 gene mutation: increased excitatory synaptic activity esp in CA1 region of hippocampus. More dendritic branching.

KO mice show reduced brain volume and mutation mice also show reduced brain volume. There may be compensatory mechanisms at play.

NB: more branches goes against less branches seen autism brains, shows that this is not the full picture.

Question 15

How was the neuroligin mutation identified and why is this significant?

Answer 15

Family where sons both had ASD. Inherited mutation from asymptomatic mum.

Despite same mutation brothers presented differently: classical and asperger’s. This heterogeneity reflects ASD and esp implicated developmental differences.

Question 16

Outline neurexin mutation present in ASD

Answer 16

NRXN1: presents with intellectual disability, developmental delay, hypotonia, facial dymorphism and risk for schizophrenia.

Mutation (or loss) = fewer PV+ (Parvalbumin, fast spiking) GABA cells and increased pyramidal cell density.

Question 17

What is the role of Shank3 in ASD?

Answer 17

Shank3 is a post synaptic densitiy protein that interacts with glutamate receptors (AMPAr) and links them to actin cytoskeleton (holds them in place).

mutation = Loss of SH3, synapse lose in CA1 (decreased spine density) and deletion shows increased dendritic complexity distal to soma and reduced spine density. Mice have reduced NMDAr expression in PFC.

In ASD: more NMDA and AMPA than normal.

Question 18

How does valproic acid cause ASD?

Answer 18

Valproic acid: inhibits histone H3 and H4 deacetylation, adds COO- group to charged lysine residues.
Acetylation neutralises positive charge on histone proteins which decreases interaction of N termini of histones with negative phosphate group = euchromatin, increased gene transcription.
Therefore, causes increased gene expression seen in ASD.

VPA also alters GSK3 activity

inhibits GABA transaminase which deactivates GABA: GABA is excitatory in development so lack of deactivation means excess excitation in developing brain.

Question 19

Changes to GABA in ASD in developed brain

Answer 19

GABA interneurons “the parvalbumin (PV)+ Chandelier (Ch) and PV+ Baskets cells (Bsk) cells, are decreased in the prefrontal cortex in autism.

VPA rats see same effects in cerebral cortex (Liu et al., 2018)

Question 20

Outline valproic acid animal model for ASD

Answer 20

400mg/kg exposure causes 3 behavioural characteristic ASD traits (Chaliha et al., 2020)

1) reduced social behaviours
2) increased repetitive, stereotyped movement
3) increase in behaviours that reflect cognitive rigidity

Also increased tactile sensation and have sleep abnormalities.

Question 21

Is VPA model valid?

Answer 21

Yes: face validity (behaviours - sleep, social) and construct (children exposed to VPA suffer fetal valproate syndrome with some developing ASD - mimics single aetiology, VPA is antiepileptic).

No: only representitive of single aetiology, ASD is heterogenic. Male VPA rodents show more robust social impairments and more stereotypies whereas females spend more time in social interaction than control (is this skewed towards men?).

pharmacological? ( not possible as no drug to treat ASD… however, korean red ginseng has been shown to improve social behaviour in rats)

Question 22

VPA and social novelty

Answer 22

VPA rodents have decreased preference for novelty in both social and object domains.

This is similar to humans and may reflect rigidity, also hypothesised to be due to memory impairment. Eg - spatial learning and neuronal loss found in VPA rodents.
CA1 is changed in ASD

Chaliha et al., 2020

Question 23

What drugs are used to treat VPA?

Answer 23

0 FDA approved to treat autism but antipsychotics

“aripiprazole and risperidone, principally target the accessory traits of irritability and aggressiveness”

Question 24

VPA and gut microbiome

Answer 24

VPA: reduced fecal microbiome richness (diversity) and changed gut micro composition as well as altering metabolite potential of fecal as seen in ASD patients.
Lack of micro (rodent experiments in germ free) = differential gene expression, lack of preference for spending time with other mouse vs alone.

Similar to ASD as: differential effects in males and females, ASD suffer gastointestinal probs and changed gut microbiome due to increased permeability of BBB.

Question 25

‘Couldn’t see the forest for the trees’ ASD?

Answer 25

Stronger image center bias regardless of object distribution (possible due to lower saccade velocity), reduced saliency for faces and locations but increase in pixel-level saliency at expense of semantic level (wang et al., 2015)

Focus on detail means that they cannot see the full picture.

Supported by faster detection of single targets embedded in cluttered displays and relative insensitivity to number of distractors. Despite this cannot identify global direction of movement (general direction crowd of people moving).
Robertson and Baron-Cohen, 2017

Question 26

Outline auditory perception in ASD

Answer 26

Children with autism often show difficulty discerning the relative presentation order of two closely occurring tones and show delayed evoked neural responses to auditory tones compared with typically developing children (Robertson and Baron-Cohen 2017)

Question 27

Music therapy for ASD

Answer 27

Music experience causes participants to shift through verbal and non communication. means for verbal people to access sensory experiences andfor people without spoken language to interact communicatively without words. It enables all to engage on a more emotional, relationship‐oriented level than may be accessible through verbal language.

Motor timing and sensorimotor impaired in ASD help treat this.
Another theory is that mothers voices are musical to shape understanding.

Cochrane review by Geretsegger et al., 2022: moderate evidance that reduces ASD severity and improves quality of life immediately post intervention however no evidence of changed in social interaction.

Question 28

People with ASD often have altered sensory perception. Why is this important to study?

Answer 28

Could serve as early diagnostic markers (earlier treatment) as present before stereotypies and altered social communication.

Shown to be largely genetic as parents and siblings of ASD have higher levels of self reported sensory traits.

Could be used to classify ASD into more homogenous groups.

Question 29

How does tactile sensation differ in ASD?

Answer 29

Results are varied: some say more, similar or less than neurotypical.

One difference in autistic tactile perception is well replicated: whereas control individuals present worse detection thresholds for stimuli that gradually increase in amplitude over time into a detectable range (reflective of dynamic thresholds) relative to acute stimuli (which require static thresholds), dynamic presentation does not impair tactile sensitivity in individuals with autism”
Thought to be from reduced feedforward inhib (Robertson and Baron-Cohen, 2017)

Question 30

How is temporal and multisensory sensation different in ASD?

Answer 30

Elongated window of audio-visual temporal binding and more likely to perceive asynchronous events as synchronous.

Robertson and Baron-Cohen 2017

Question 31

How does GABA alter sensation?

Answer 31

E/I imbalance in Autism: mice with mutations in Mecp2, Gabrb3, Shank3 or Fmr1 all demonstrate tactile sensitivity ansd has been linked to loss ofGABA AR mediated inhibition.

mecp2 KO (Rett’s) show reduced amplitude of visually evoked responses in V1.

Question 32

What does VPA cause in utero rats behaviour?

Answer 32

1)decreased number of social explorations and increased latency to social behaviors, both pointing to social deficits

2) increased locomotor and repetitive/stereotypic-like activities combined with lower exploratory activity, suggesting increased locomotor stereotypies and compulsive behaviors

3)lower sensitivity to pain at the spinal and supraspinal (only in adult-hood) levels and higher sensitivity to non-painful stimuli, suggesting sensory system deficits

4)lowered acoustic pre-pulse inhibition, pointing to attention and information processing deficits and impaired sensorimotor gating that could result in stronger reactions to environmental stimuli and ultimately lead to increased repetitive, stereotypic behaviors.

5)delayed maturation (late eye opening), lower body weight, delayed motor development, and delayed nest-seeking response

Question 33

What does VPA do to brain of rats?

Answer 33

Increased local connectivity (weaker and more synapses in layer V and less excitable cells)

Increased dendritic branches

Decreased NLg3.

Question 34

How does DSM V classify ASD?

Answer 34

Persistent Social impairment and restrictive behaviour (often present since childhood).

Question 35

Educational poverty and ASD

Answer 35

Rates of ASD increase due to lack of money in education.

Some people with ASD who could cope due to improved school environments can no longer and therefore more diagnosis of ‘less severe’

Question 36

State theory behind why ASD have social communication deficits

Answer 36

Assume that other person knows what they are thinking and therefore speech is redundant.

This why children will have fits as they assume their needs have been vocalised but have not been.

Question 37

ASD and OCD

Answer 37

in ASD they execute repetitive movements to ease anxiety (they can control doing the same thing over and over again).

OCD: person does not want to repeat.

Question 38

Why do ASD people: rock with hands over ears and eyes closed?

Answer 38

ASD can be thought of as an information processing disorder = take in too much info that overload.

ears: control audition/prevent sound
closed eyes: control vision/prevent
rocking: control proprioception as often reported to have increased or decreased proprioception.

Question 39

Outline comorbidity of ASD and pain

Answer 39

ASD comorbidity with chronic pain, double neurotypical at 16%

SCN9A: encodes voltage gated na channel in PNS (dorsal root ganglion, where sensory neurons cluster).

• there are several variants: some of which decreased rate of AP firing.
• However, gain of function has been implicated in paroxysmal pain disorder (not ASD)
• So ASD goes against prev literature.

Also interesting to note: shank3 mutations cause pain insensitivity so thought that in ASD there is altered pain perception not necessarily higher (seen by some painful behaviours ASD exhibit).

Question 40

Prevalence and sex differences

Answer 40

Over 1% worldwide with higher proportion of men (up to 16:1)

Women diff phenotype and more likely to be misdiagnosed with anxiety. Better masking

Question 41

Extreme male brain theory?

Answer 41

Baron-Cohen 1999

Foetal testosterone impacts downstream targets (dendritic spines and synapse formation).

Evidence…
1) men more systematic
2) women more empathetic

Obvs this theory not accepted anymore and also got a lot wrong saying ASD better at spatial learning when tend to be worse