Lecture 15: Neuropsychiatry and the Gut Microbiota 2 Flashcards

1
Q

Which tools are used to study genetic basis of disease?

A

genome wide association studies and exome sequencing of parents / affected patients / unaffected siblings

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2
Q

What do genome wide association studies tend to miss?

A

rare, high impact mutations

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3
Q

When does exome sequencing work best?

A

if you have the whole triad of parents, affected patients and unaffected siblings

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4
Q

What does exome sequencing of parents / affected patients / unaffected siblings identify?

A

copy number variations, single nucleotide polymorphisms (SNPs), within gene deletions

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5
Q

What do protein-protein interactions show?

A

strong overlap between diseases

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6
Q

What does each gene cluster produce?

A

proteins with related functions

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7
Q

What happens once a mutation has been identified?

A

generate an animal model expressing the mutation identified by sequencing and test its behaviour to see if that behaviour mimics what is seen in humans with the mutation

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8
Q

What happens if the animal mutation behaviour does mimic what is seen in humans with the mutation?

A

test the physiological and neural circuit changes that might underline the alterations in behaviour and then generate animals models in which the relevant proteins are up- or down-regulated to begin to determine the function of the protein

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9
Q

What are some examples of biological models?

A

cultures expressing the mutant gene to identify changes in cell biology produced by the mutation
zebrafish much more complex with a vertebrate CNS, but relatively easy to manipulate and short breeding and embryogenesis cycle

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10
Q

What must an animal model have to be really useful?

A

construct validity, face validity and predictive validity

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11
Q

What is construct validity?

A

expresses the mutation implicated in the genetic studies

in the same or equivalent locations

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12
Q

What is face validity?

A

exhibit behaviours considered characteristic of the disease

in the case of ASD: aggression, stereotyped behaviour and abnormal communication

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13
Q

What is predictive validity?

A

treatments that change behaviour in the model should produce similar outcomes in human patients

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14
Q

What are problems with mouse models?

A

human brain is much more complex
predictions about the results of treatment made from rodent studies usually fail in humans when applied to brain disorders
the lifestyle of laboratory mice is very different from even the most confined of humans

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15
Q

Which proteins are commonly mutated in ASDs?

A

synaptic proteins of which their central role is maintaining synapse function (neuroligin-neurexin)

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16
Q

What is ASD associated with?

A

up to 90% of ASD patients reported to have GI dysfunction, notably constipation

17
Q

What complicates interpretation of ASD gut issues?

A

ASD patients are often very selective in what they will eat

18
Q

What might cause constipation in ASD patients?

A

ASD patients might engage in “faecal withholding”

changes in ENS function might parallel changes in CNS function

19
Q

Are all mutations relevant to ENS?

A

no, some mutations might not present in the ENS and proteins that regulate spine morphogenesis may have alternative functions in the ENS

20
Q

Why are neuroligins and neurexins relevant?

A

ASD-causing mutations in these genes would be expressed in ENS
mutations causing other neuropsychiatric diseases would also be expressed

21
Q

Why is neuroligin 3 important?

A

two mutations in neuroligin 3 produce ASD

1: gene deletion
2: point mutation that substitutes a cysteine for an arginine at position 451 in protein

22
Q

What neurons do NL3 R451C mice have more of in comparison to their wild type litter mates?

A

more myenteric neurons and more nitric oxide synthase neurons in jejunum

23
Q

Does ENS development differ between NL3 R451C mice and their wild type litter mates?

A

yes and this may be expected to have functional consequences

24
Q

What are the consequences of altered ENS development in NL3 R451C mice?

A

small intestinal transit in vivo is accelerated in these mice
weight of caecum is reduced and associated with altered lymphoid tissue in caecum

25
Q

Does the faecal microbiome in 5 week old NL3 R451C mice differ from wild type? What does this mean?

A

yes, this means that mutations in synaptic proteins that lead to ASD produce GI dysfunction