Autism spectrum disorder (finished Flashcards
How is ASD defined (diagnosed)?
Deficits in these 2 core domains (3 symptoms)
a) Atypical social behaviour
b) Disrupted verbal & non-verbal communication AND restrictive interests & repetitive behaviours
Onset before age 3
What is used in order to diagnose autism?
DSM- V = diagnostic and statistical manual of mental disorders
How often is a delay in spoken language seen in ASD cases?
Delay in spoken language seen in ~50% of cases
What 3 previously separate diagnoses does the DSM-V combine into ASD?
- ‘Autistic disorder’
- ‘Asperger’s disorder’
- ‘Pervasive developmental disorder - not otherwise specified (PDD-NOS)’
What sort of therapy is available for patients w ASD?
Therapy restricted to behavioural intervention as so many different traits associated with ASD and the origin is hard to treat
Can benefit IF received early
What are the FDA approved drugs for treating ASD and what does each one aim to do?
Antipsychotics:
- Risperidone- treats aggressive and repetitive behaviour
- Aripiprazole- reduces irritability
What are the 2 main treatments for ASD?
- Behavioural intervention therapy
- FDA approved drugs
What is the issue with using drugs to treat ASD?
Drugs don’t treat core social deficit just the behavioural symptoms managed
What is the prevalence of ASD in the early 1990s vs today?
Early 1990s = 1 in 1,000- diagnostics were not very developed
Today = est. 1 in 68 children under 8 in the USA
What is the prevalence of ASD in males vs females?
- 1 in 42 for males
- 1 in 189 in females
(5 fold for males)
What are the prevalent comorbidities of ASD?
- Motor deficits
- Sleep abnormalities
- Gastrointestinal disturbances (50%) (gastrointestinal microbiome partly responsible for ASD)
- Epilepsy
What level of intelligence is generally found in children w ASD?
How about the 2 minorities of intelligence?
MOST ASD children have normal intelligence
35-50% have intellectual disability - defined as IQ <70
Small minority - have remarkable memory/intellect e.g. Einstein
What is the neuropathology of ASD?
- No common macroscopic or microscopic neuropathology
- Ne specific brain region or cell type implicated
(So cannot diagnose w brain imaging)
How does head size differ in ASD?
~20% larger head size
Are there any biomarkers for ASD?
No biomarkers –> means no prediction at birth
How can an EEG be used for diagnosis?
Eye tracking movements (eye contact issues) & EEG can be helpful for diagnosis
What is the group of drugs that is used to treat ASD?
They are antipsychotics
Name the 3 core autism symptoms
- Social deficits
- Language impairment
- Repetitive behaviours
Name the 6 associated neurological issues in ASD?
- Seizures
- Sleep deficits
- Mood
- Anxiety
- Hyperactivity
- Attention (last 2 link to ADHD as a related disorder)
Name the 2 associated systemic issues in ASD
- GI disorders
- Immune dysfunction
What are some of the typical early traits in ASD seen in children?
- Inability to relate to children or adults
- Poor speech or lack of speech
- Inappropriate crying/laughter
- Oversensitive or undersensitive to sound
- Inappropriate playing w toys
- Difficulty dealing w changes in routine
- Oversensitive or undersensitive to touch
What % of cases do genetic conditions contribute to ASD?
Rare genetic conditions contribute to 3% of ASD cases
Very small fraction of children w ASD
What % of children with an autistic sibling develop ASD?
20%
Certain degree of inheritance
What is a De novo mutation?
A mutation that is present in the offspring but not inherited (absent) from either parent- occur after fertilisation
How can a De novo mutation cause ASD?
How frequent are they?
Coding differences occurring after fertilisation (not inherited from either parent)
Occur in 5-10% of all cases
A sporadic form - not inherited
How often do genetic mutations cause ASD?
80-85% = no clear genetic cause
- 3% mendelian single gene inherited
- 5% chromosome anomalies & CNVs
- 5-10% De novo single gene mutations
How can chromosome anomalies & CNVs cause ASD & how common are they?
5% of cases caused by copy number variations
Large sections of the genome replicated/deleted
Which gene has been found to be affected by de novo mutations in ASD?
The gene producing the protein TRIO
It is responsible for the early formation of dendritic spines of glutamatergic neurons
What % of children w an autistic sibling develop ASD?
20% = certain degree of inheritance
What is the main factor that results in ASD?
predominantly due to difficulties in early development that is mainly neuronal networks which then in adulthood will be showing as behavioural abnormalities
What are the 3 levels at which ASD develops on?
- Neuroanatomical
- Systems-level
- Cellular and molecular
What are the neuroanatomical ways that ASD differs?
- Brain growth- ASD have larger brains in early stages but throughout development this normalises
- Cortical columns- neurons form these networks in very early stages but these are altered in ASD (malfunctions)
How does brain growth differ in those w ASD?
Children w ASD tend to have larger brains
Thru development this normalises again in adolescence
How do cortical columns differ in those w ASD?
- There is disorder of neuronal connectivity esp in the cerebral cortex
- Malfunctions occur in the formation of these early networks
How does pathfinding differ in ASD both prenatal & postnatal?
Prenatal –> neuronal migration & axonal pathfinding is different
Postnatal –> dendritic development, synaptic pruning & neurogenesis differs- involved in forming networks in brain
What are the systems-level ways that ASD differs?
- White matter tracts & functional connectivity
- Balance of excitations/inhibition
How does the balance of excitations/inhibition lead to ASD?
Some genes cause different prenatal pathfinding
So more excitatory than inhibitory neurones forming
What are the genes involved in systems-level ASD causes?
- NRXN1
- NLGN2&3
- SHANK3 (excitatory) - has been shown to have particular links to ASD
How many genes are involved in malfunction of circuits in ASD?
> 100 susceptible genes covering on pathways involving synaptic transmission
(Different genes may contribute to the 3 distinct symptoms)
What are the cellular & molecular ways that ASD differs?
- Activity-dependent protein synthesis
- Neuronal activity
- Neuronal cell adhesion
What are the genes found at a cellular & molecular level that contribute to ASD & what do each of them do?
- SCN2A &1A - related to VGSCs
- GRIN2A & B - NMDA receptors
- GRIK2 - kinase receptors
- CACNA1C & H - VGCCs
(Genes encoding for these proteins shown to be associated w ASD)
What does the biological convergence of genes & pathways affect?
- Synapse formation
- Neuronal activity
- Neuronal cell adhesion
What 6 areas of genes are affected in ASD?
- Synaptogenesis
- Protein synthesis
- Chromatin remodelling & transcription
- Protein degredation
- Phospholipid homeostasis
- Cytoskeleton dynamics
What is synaptogenesis?
= formation of synapses between neurons
What are the genes that are affected in synaptogenesis in ASD?
- Neurolexin
- Neuroligin
- Neurobeachin
- DAT
- mGluR
- Neulexin IV
- Synaptojanin
What is the gene in ASD that affects both cytoskeleton dynamics & synaptogenesis?
SHANK gene
What is the main function of neuroligin and neurexin?
= cell adhesion proteins responsible for forming appropriate synaptic connections
What are neuroligins + their function?
= synaptic cell-adhesion molecules at postsynaptic neuronal membranes and interact with either glutamate (NMDA receptors – excitatory) or GABA receptors (– inhibitory) to the synapse and maintain the excitatory/inhibitory balance
What is a neurexin?
= components of the presynaptic neuronal membrane and their intracellular domain interacts with proteins involved in exocytosis- to allow synaptic vesicle recyling
Explain how immunostaining was used to see the effect of neuroligin + results
Effect neuroligin by introducing a mutation (R451C) will alter GABAergic activity
Can look at via immunostaining- stain for VGAT in the presynaptic vesicles
- mutate protein = increased signal of GABA presynaptic neuron (more green dots)
= neuroligin is responsible for expression of GABAergic neurons
Explain how electrophysiological data was used to see the effect of neuroligin + results
Can study functional effects of same mutation
can measure spontaneous activities of neurons:
- EPCs = excitatory postsynaptic currents mediated by glutamate
- IPCs = inhibitory postsynaptic currents mediated by GABA
Increased activity of GABAergic activity following mutation = more GABA activity as neuroligin affected = direct link
Explain how behavioural was used to see the effect of neuroligin + results
Measure social interactions in mice via time spent with a partner
But mutants spent less time interacting with their partners
What other protein is important in ASD?
dopamine receptors
Describe an experiment that suggests D2 receptors are involved in ASD
Human brain samples have been used for experiments with a radio-label (mRNA)
ASD vs controls = Dopamine receptor 1 is unaltered but DR2 in ASD have higher levels of these receptors
What do D2 receptors lead to and where are they found?
= pre and post synaptic neurons- high levels in striatum
lead to reduction in cAMP signalling
What is another protein associated with ASD?
DAT = dopamine transporter
Describe an experiment that suggests DAT is involved in ASD
Mutation inserted into Human DAT protein (T356M)- showed DAT has impaired ability to transport dopamine (shown in graph)
No effect on expression (shown on bar graph)
What is this multi sequence alignment showing?
threonine = preserved across different species- suggesting important function involving DAT
What happens when there is a T356M mutation and where is it located?
Knock threonine amino acid = reduce activity of DAT as mutation is located on transmembrane domain 7
Describe an experiment on drosophila that suggests DAT is involved in ASD
Drosophila- assess activity
Put flies into tube with infrared beam going through, which measures how many times fly crosses beam = readout of fly activity
Insert T356M into flies or knockout DAT = activity increases / hyperactive
Outline the causes and risk factors of ASD
Is age a risk factor for developing ASD + explain?
Yes- increased risk with increasing maternal age = age 25 to 40 the risk of developing ASD doubles
- same applies to male- if father is >10 years older than mother = increased risk
What is another neurotransmitter that is implicated in ASD?
serotonin
How is serotonin implicated in ASD?
- hyperserotonemia
What is hyperserotonemia and how many people with ASD does this occur in?
Elevated whole blood serotonin levels (particularly in platelets)- Elevated whole blood serotonin levels (particularly in platelets) occur in approximately 25% of children with autism
What other disorders are associated with hyperserotenemia?
OCD
What is hyperserotonemia caused by?
Increased 5-HT production by enterochromaffin cells in the intestine, increased uptake of 5-HT into the platelet, decreased metabolic breakdown of 5- HT
Outline some evidence that suggests 5-HT is involved in ASD
Tryptophan depletion which decreases synaptic 5-HT, worsens repetitive behaviours and irritability in autism
Outline some neuroimaging evidence that suggests 5-HT is involved in ASD
Neuroimaging studies found decreased 5-HT2A receptor binding in adults with Asperger’s syndrome and parents of children with autism
What other 5-HT mechanisms have been shown to altered in ASD?
deactivation mechanisms- SERT and MAO-A
What does the genetic knock out of SERT do?
Genetic knock-out of SERT alters brain development, including overall brain growth and interneuron migration into the cortex
- affected early on during development = impacts on path finding and synaptogenesis events
Name a treatment involved in increasing serotonin levels in the brain and does it have any benefits for ASD?
SSRIs = have little therapeutic benefit on ASD
Where are serotonergic neurons expressed?
expressed in dorsal and median raphe neurons
What is gene encoding SERT and what chromosome is it located on?
Gene encoding serotonin transporter [member of’solute carrier family 6’(SLC6A4)] on chromosome 17 = mutation in this potentially leads to ASD
How is the SLC6A4 gene altered in ASD?
Promotor region of the SLC6A4 gene contains a polymorphism leading to “short 14” and “long 16” repeats; the short 14 repeat reduces transcription and is associated with anxiety-related traits and altered brain structure.
Describe how the most common SERT amino acid variant was examined in mice
SERT Gly56Ala knock-in mouse (=mutation reducing SERT activity) has elevated blood serotonin, altered serotonergic raphe neuron firing (reduced firing)
+ altered social behaviours- 3-chamber crawley sociability test:
= Put mice into 3 chambers
1. one chamber has mouse in glass
2. One chamber has no mouse in glass
3. Mouse placed into middle chamber and allowed to explore
= usual behaviour = mouse spends time investigating chamber with other mouse
Measure time mice spent investigating- compare times with wildtype and those with Gly56Ala mutation = mutant mice reduced time spent investigating other mouse
How is the Gut brain axis involved in ASD?
Changes in the gut microbiota composition and resultant altered gut-derived microbial products and neurotransmission can over-activate the immune system producing increased oxidative stress and impact on serotonin signalling.
Describe the basic structure of the gut-brain axis
- microbiome in gut produces many chemicals- some beneficial and some toxic
- Communcation via vagus nerve that signals from the gut to the brain
- communication via bloodstream from gut into brain
Gut biota can produce a huge range of chemicals including serotonin, inflammatory molecules etc - which signal into brain
Happens in both mammalian systems and drosophila
Outline some gastro-intestinal disturbances associated with ASD
Whole range of gastro-intestinal disturbances in ASD- which specifically interact with the serotonergic pathways
- Certain bacteria able to intefere with cascade of serotonin synthesis e.g. clostridium
Which neurotransmitters are effected (produced/interferred with) by the gut brain axis
Whole range of neurotransmitters
- Noradrenaline(Escherichiaspp (E coli),Bacillusspp.andSaccharomycesspp.)
- Dopamine (Bacillusspp.)
- Serotonin- (Candidaspp.,Streptococcusspp.,Escherichiaspp. (E coli) andEnterococcusspp.)
- GABA (Lactobacillusspp. andBifidobacteriumspp.)
- Acetylcholine(Lactobacillusspp.)
How is the gut-brain axis implicated in ASD
- changes in microbiome
- = changes activity of endochromaffin cells- produce neuro-inflammatory molecules
- Via vagus nerve this is signalled to brain + also can be via bloodstream to brain where the BBB is crossed = cytokines are able to interfere with neuronal function
= cascades responsible for dis-development of the brain- that has worse impacts if it occurs in early development
Name some examples of bacteria that have been shown to be beneficial to neuronal development + what do they do?
- Lactobacillus reuterihas the capacity to upregulate plasmaand brain levels of oxytocin (increases social behaviour in mouse models of ASD).
- Lactobacillus rhamnosusproduces GABA and regulates GABA receptors in the brain.
- Bifidobacterium longumupregulates brain-derived neurotrophic factor (BDNF), augments neuronal plasticity in the enteric nervous system (ENS) and reduces anxiety and depression-like behaviours in mice.
- Bacteroides fragilisimproves anxiety-like behaviour, repetitive behaviour and communication in mice.
Describe an experiment which shows the effect of bacteroides fragilis on ASD
Bacteroides fragilis used as a treatment can releive autism like behaviour abnormalities in mice:
1. Immune activation induced in mother during pregnancy = injected with inflammatory molecule, so offspring exposed to maternal immune activation
2. Then measured anxiety-like behaviours in off-spring- had open platform that is usually fully explored but if anxious they hide
3. Hiding behaviour was associated when off-spring exposed to maternal immune activation
4. But treatment with bacteroides fragilis = increase in exploratory behaviour despite still experiencing maternal immune activation = suggests early developmental abnormalities can be reversed by beneficial bacteria
