Autism

Question 1

why is autism considered a pervasive developmental disorder?

Answer 1

because it is exhibited early and persists

Question 2

what symptoms did leo kanner describe in 1943?

Answer 2

a cohort of children that could noti relate (social dysfunction), poor or stunted language skills (communication), pront to repetitive behaviours (restricted behaviour)

Question 3

who coined the term autism? when?

Answer 3

1943 Leo Kanner

Question 4

unaware of Leo Kanner, what term did Leo Asperger use?

Answer 4

autistic psychopathy

Question 5

what are the symptoms of the autistic triad?

Answer 5

• impaired social interactions
• impaired restricted activity particularly focussed to inanimate objects
• verbal communication or reduced language skills

Question 6

what two features of the autistic triad are present in aspergers?

Answer 6

impaired social interaction
and
impaired restircted activity particularly focussed to inanimate objects

Question 7

what major cognitive syndromes can have bahviours that appear autistic?

Answer 7

Rett’s and Fragile X

Question 8

what is fragile X syndrome and what is it caused by ?

Answer 8

mental retardation with modest autistic phenotype
occurs in 1/5000 (males>females)
caused by a mutated RNA binding protein (fragile x gene)

Question 9

what is Retts syndrome and what is it caused by ?

Answer 9

a rare genetic neurological and developmental disorder that affects the way the brain develops. This disorder causes a progressive loss of motor skills and language.
similar early symptoms (pre-school) progresses to mental retardation
1/12500
caused by MECP nuclear methyl DNA binding protein

Question 10

what is Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS)?

Answer 10

a group of disorders characterised by impairment in the development of social interaction, verbal and non-verbal communication, imaginative activity and a limited number of interests and activities that tend to be repetitive
low level autism spectrum, more common but better prognosis
1/200

Question 11

how does Heller’s childhood disintegrative disorder compare to autism?

Answer 11

normal development followed by dysfunction in many areas beyond seen in autism
social skills less disrupted that classic autistic
severe decline in language sjills
1/100000

Question 12

give the three major indicators of autism in the diagnostic and statistical manual (DSM-5)

Answer 12

PERSISTENT DEFICITS IN SOCIAL COMMUNICATION AND SOCIAL INTERACTION ACROSS CONTEXTS,
NOT ACCOUNTED FOR BY GENERAL DEVELOPMENTAL DELAYS, (AND MANIFEST BY 3 OF 3 SYMPTOMS)

RESTRICTED, REPETITIVE PATTERNS OF BEHAVIOR, INTERESTS, OR ACTIVITIES (AS MANIFESTED >2 OF 4 SYMPTOMS)

SYMPTOMS MUST BE PRESENT IN EARLY CHILDHOOD BUT MAY NOT BECOME FULLY MANIFEST UNTIL SOCIAL DEMANDS EXCEED LIMITED CAPACITIES).

Question 13

what is the Sally Anne Test ?

Answer 13

A test to recognise empathy and associated social skills in the young

Question 14

why might autism be more prevalent or more often diagnosed in the male population?

Answer 14

females may better mask the symptoms resulting in late or unidentified diagnosis

Question 15

evidence suggests a general difference at a population level in male and female beavhiour. what differences do they have in terms or empathising and sympathising ?

Answer 15

Human females Empathize: Do well in behavioural scores of ability to predict and respond appropriately to others (normally peoples) mental state.

Human Males Systemize well: predict and respond to the behaviour of nonagentive deterministic systems by predicting rules that govern the system.

Question 16

what potential correlates/postulates are there for the difference in empathising/sympathising between males and females?

Answer 16

Male have increased white matter subserving local neuronal connections that underpin systemizing the increased proportion of local circuits promote focussed behaviour. In an extreme male brain (Autistic) may underpin focussed and act against empathizing nerve activity.
Argues for a role in prenatal androgens exposure in mechanisms that give rise to the autistic phenotype. Androgen production does impact on early brain development

Question 17

how does scoring linkage in behaviours in general population argue for fractionated disorder ?

is there an individual component that comes together to give the full presensenation or it it a single point that generates the outcome

Answer 17

Scoring the various traits – if you do that you see patterns or association but not significant linkage suggesting they are individually expressed.
Score play, verbal communication and rigid/repetitive behaviours in general population.
Linkage levels Social/verbal>verbal/repetitive>social/repetitive but non showed a significant linkage.
Normal Individuals show dysfunction (difficulty) in one aspect of triad.
Poor expression of the individual traits of the triad in autism (e.g. Dysfunction or repetitive behaviour appears after verbal/social). Not complete fractionation as some socially biased test tease out associations.
Genetic inheritance of individual traits in the triad (in twin studies) argues for fractionation of traits.

Question 18

what brain regions could be involved in the social traits of autism?

Answer 18

cortical regions: medial frontal cortex, temporparietal jjunctions, temporal suculus and poles

Question 19

what brain regions could be involved in the verbal traits of autism?

Answer 19

dysfunction in voice centres of the cortex

Question 21

what brain regions could be involved in the repetitive traits of autism?

Answer 21

caudate putamen

Question 22

what evidence infers that autism is a disorder underpinned by changes in brain structure and function?

Answer 22

• Electroencephalograms in autistics identify unusual patterns of electrical activity.
• Reinforced by the strong association with seizures (about 30%) in autism.
• Changes in brain size relative to control populations (slow neonatal and rapid post-natal growth).
• Series of imaging and post-mortem studies define abnormal development and connectivity but in a non-obvious way.
• cell numbers, size and density change

Question 23

studies in the 70s/80s looked for structural differences and found a range of evidence, yet not one thing that is different. the unifying theory led to an initial answer to the biological basis of autism

Answer 23

No unifying theory for what is changing in people with autism – there is a brain structure function change that underpins the expression that leads to the diagnosis of autism
So the biological basis of autism seems to be underpinned and explained by a change in brain function but without any specification about where this arises or the specifics of it

Question 24

what age do you begin to see the symptoms of autism

Answer 24

5-6 years

Question 25

what is a sign of synaptic maturation?

Answer 25

Mature synapse relatively stable
Explicit adhesion contacts between the pre and post synaptic cells is a sign of maturation and makes them relatively stable to the immature synapses

Question 26

what is the coincidence of autism in monozygotic twins?

Answer 26

80-90%

Question 27

how can we track the inheritability of genes?

Answer 27

by tracking mutations and chromosomal rearrangments through pedigree in humans or breeding programs in animal models.
also Linkage or association using markers (eg SNPs) to to track regions of the genome associated with a pehnotypic trait and infer molecular association

Question 28

what are SNPs and how can they help in understnading genetic underpinning in autism?

Answer 28

Every 500bp you will find a single nucleotide polymorphisms (random). This is fixed through populations, this enables us to track and catalogue where these SNPs exist.

Take 2000 SNPs in two populations autistic and neurotypical and catalogue where they lie, make comparison, become quantitative where you can track different parts of the genome which are more or less likely to fall into association with a certain group of individuals and that association then calls up regions within the genome that mark out genetic elements that may be important in the expression of the overriding diagnosis
Do hybridisation

Question 29

describe how the genome wide association studies (SNP penetrance) helps to understand the disease and its genetic underpinning?

Answer 29

This approach lead to a clearer definition of where the genetic variation in autistic spectrum disorder is identified
* There are individuals with rare highly penetrant variations where there is a single SNP probably identified by sequencing approaches in which the disruption can be identified and used to understand the mechanism of autism
Low penetrant end - five or six or ten regions of the genome showing an association through GWAS studies. more frequent but not as penetrant, in any one individual they will not express the disorder (a collection of individuals that indicate that that variation might be important)
But both extremes increase the believe in the idea that there is a genetic determinant underpinning asd

Question 30

of the many genes implcated in ASD, what do many of them describe?

Answer 30

synaptopathy

Question 31

give some examples of the function of genes implicated in ASD that point to a synaptic basis for pathophysiology

Answer 31

• protein organisers of the synapse
• directly control chemical transmission and excitability
• cell signalling thus synapse functions
• cell-cell and synapse contacts
• developmental processes that lead to synapse formation
• control transcription and expression of other genes involved in the formation and stabilised of synapses
• regulate the cytoskeleton and form and function of dendrites
  *

Question 32

how could the genes implicated in ASD impact neural structure and function

Answer 32

Migration of neurons and elaboration or stabilization of synaptic processes (dendrites).
Cell number, cell density and connectivity.
Impact on synaptic contact and stabilization
Impact on the balance of inhibitory and excitatory synapses.

Question 33

why are cell-cell contacts important for the brain?

Answer 33

at the point of outgrowth where they have to interact with the environment to allow axons to extend processes
but also in the final step where there’s stabilisation of synaptic contacts that initially formed in early development that need to be matured to express full function

Question 34

how do genes involved in cell-cell contacts affect structure and function in autism

Answer 34

This protein pair controls an important (but not integral/required) cell cell contact and controls presynaptic nerve terminal communication with the post synaptic
In addition the biochemical entities show ability to have a general role but also show selectivity to organise either excitatory or inhibitory contact – important when you know that asd is a expression of an Imbalance in excitation and inhibition

Question 35

what is neuroligin?

Answer 35

Neuroligin is a single pass transmembrane protein that’s involved in the cell cells contact between post and presynaptic sides.

Question 36

what is the structure of neuroligin?

Answer 36

It has a transmembrane domain, a coiled domain and then a domain that has homology to acetylcholinesterase (this is only a similarity in structure and does NOT function similarly)

Question 37

what is neuroligins primary target?

Answer 37

(presynaptic molecule) neuroexin

Question 38

what is the stucture of neurexin and how does it relate to its function?

Answer 38

it has a transmembrane domain and three repeat domains that stetch out from the transmembrane into the synaptic cleft from the presynaptic site.
Its topology allows contact and adhesion and communication between the pre nerve and post (20nm cleft)

Question 39

describe the genetic complexity of neuroligin

Answer 39

Neuroligins are encoded by four distinct genes that are extensively spliced – there are four genetic elements and show huge variation from splicing
More complexity comes because in human males there’s a y linked copy of the neuroligin , an additional copy (this makes it distinct from the mouse and rat which are used as models)
Neuroligins are even more remarkable each gene has an alternative promoter that produces two distinct transcripts
In addition the alternative splicing means that there are over a thousand isoforms

Question 40

what does the genetic complexity of neuroligin mean for its function?

Answer 40

Within the pre and post synaptic contact you have two molecules that are able to organise based on the gene that is expression and the variation of differential promoters and transcripts

Question 41

what happens to mice that lack neuroligins?

Answer 41

Mice lacking neuroligins have a brain, have synapses and expected number of synapses (hippocampus/cortex).
Die because brain stem (respiratory neural network) has disrupted neural activity. Functions by a balance of inhibitory and excitatory in neural circuit - In normal brainstem inhibitory input dominates, In neuroligin deficient mouse model the ratio of inhibitory/excitatory transmission is reduced so excitatory transmission dominates.
Brain stem has normal numbers of synapses but functionally both the Glutamate (excitatory) and GABA (inhibitory) transmitters are reduced.

Question 42

what insight do neuroligin deficient mice give about the mechanism underpinning of autism

Answer 42

Synaptic dysfunction without loss of cells or synapses appears real possibility-argues for synaptic maturation playing a role in autistic condition.

potential for relevance of dysfunction in synapse-synapse contact phenomenon driving autistic phenotype by the largest linkage study of autistic pedigrees revealing NEUREXIN AS prime candidate susceptibility gene.

Question 43

which neuroligins are generally involved in organisation of GABAergic synapses?

Answer 43

neuroligin 2

Question 44

which neuroligins are generally involved in organising glutaminergic synapses

Answer 44

neuroligins 1 3 and 4

Question 46

what de novo neuroligin mutation was shown in two brothers with differential penetrance of ASD

Answer 46

The mutation was an arginine conversion to cysteine at position 451 of the neuroligin gene. That mutation mean the protein made is relatively non functional because the protein isn’t delivered to the cell surface plasma membrane and cant undergo the same cell cell contacts that is fundamental to neuroligin function

Question 47

the de novo NLG3R415C mutation was tested in a mice model.
what did this show about the veracity of animal models?

Answer 47

it showed how a single gene can effect a broad range of behavioural traits
because the mice had different effects, one team showed “Reports a strong social interaction deficit behaviourally”. whereas another team “Refutes any effect of social interaction behaviour”

Question 48

what were the effects of NLG3R451C mutation in humans

Answer 48

• relatively normal synapse number
• normal synapse structure
• increased inhibtion
• impaired social behaviour
• modified (improved) learning

Question 49

what are the effects of neuroligin-3 knockout in humans?

Answer 49

• relatively normal synapse
• increased metabotropic glutamate receptor
• disrupted plasticity in the cerebellum

Question 50

how did research systematically test the effect of neuroligin 3 mutations and knockouts with emphasis on repetitive behaviours?

Answer 50

Using an experimental model for motor learning – the rotor rod. A rod revolves, put animal onto it and spin until it falls off.

Question 51

what did the rotor rod experiement on NLG mutant and knockout mice show?
what does this suggest

Answer 51

at first you see no change between the knockout and the NLG-3R451C mutation vs the wildtype however as you increase the speed of rotation the difference becomes more apparent. (requires mr efficnet learning process)
in both cases once the speed was increased, those lacking or expressing mutated NLG3 showed improved learning compared to the wild type. – suggesting that a convergent aspect of null function in neuroligin could be seen in a discrete behaviour such as repetitive learning.

Question 52

when the NLG3 gene was reintroduced into specific regions in knockout mice what area of the brain showed the rescue of behavioural loss

Answer 52

reintroduction of the gene into brain regions key in motor control
Rescue against the behavioural loss was found when the gene was reintroduced into the ventral striatum (nucleus accumbens) (not traditionally associated with motor learning)

Question 53

what are the differences between the neurons in the ventral striatum?

Answer 53

both are activated or inhibited from glutamate or GABAergic inputs
neuroligin 3 is expressed post synaptically on both

however one expresses D1 dopamine receptors and the other expresses D2 dopamine receptors
they have difference downstream targets
the effect of NLG3 loss of function differs - GABAergic input is reduced to the D1 neurons (disinhibition)

Question 54

what therapies are available for autism?

Answer 54

behavioural therapies to induce ‘behavioural plasticity’
1. Sensory or play therapies to refine behaviour by bringing individual out oneself.
2. Encourage interaction with environment and others (often involve carer programs).
3. Cognitive therapy: identify deficiencies, instil awareness and teach or school affected individuals to develop strategies to overcome these.

drug therapies based on triad
1. Target neurochemistry that underpin autistic triad.
2. Transmitter pathways that underlie behavioural disorders associated with autism
3. Organic interventions associated with vitamin supplements or diet include Mg2+, vitamin B6 and B12.

Question 55

what drugs can be used to target the autistic triad?

Answer 55

Serotonergic and dopaminergic drugs can act on social impairments and stereotypic behaviour (e.g. Haloperidol (dopamine receptor antagonist) and Resperidone (dopamine and serotonin antagonist).
Several selective serotonin reuptake inhibitors (SSRIs e.g. fluoxetine) been used to target the repetitive behaviours associated with autism.
Isolated indications of successful use of lithium, valproate and carbamazepine
Sleep disorders and aggressive behaviour are seen with autistic individuals and have been treated with propranolol, or clonidine (adrenergic antagonists).

Question 57

how does the effect of neuroligin 3 loss of function (KO and R451C) effect medium spiny neurons in the ventral straitum

Answer 57

Neuroligin 3 loss of function (KO and R451C) reduces inhibitory signals from GABA releasing onto D1 but not D2 neurons (no affect to excitation).

Distinct synapses are not equally dependent on NLG-3.