Lecture 15: Neuropsychiatry and the Gut Microbiota 2 Flashcards
Which tools are used to study genetic basis of disease?
genome wide association studies and exome sequencing of parents / affected patients / unaffected siblings
What do genome wide association studies tend to miss?
rare, high impact mutations
When does exome sequencing work best?
if you have the whole triad of parents, affected patients and unaffected siblings
What does exome sequencing of parents / affected patients / unaffected siblings identify?
copy number variations, single nucleotide polymorphisms (SNPs), within gene deletions
What do protein-protein interactions show?
strong overlap between diseases
What does each gene cluster produce?
proteins with related functions
What happens once a mutation has been identified?
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
What happens if the animal mutation behaviour does mimic what is seen in humans with the mutation?
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
What are some examples of biological models?
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
What must an animal model have to be really useful?
construct validity, face validity and predictive validity
What is construct validity?
expresses the mutation implicated in the genetic studies
in the same or equivalent locations
What is face validity?
exhibit behaviours considered characteristic of the disease
in the case of ASD: aggression, stereotyped behaviour and abnormal communication
What is predictive validity?
treatments that change behaviour in the model should produce similar outcomes in human patients
What are problems with mouse models?
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
Which proteins are commonly mutated in ASDs?
synaptic proteins of which their central role is maintaining synapse function (neuroligin-neurexin)
What is ASD associated with?
up to 90% of ASD patients reported to have GI dysfunction, notably constipation
What complicates interpretation of ASD gut issues?
ASD patients are often very selective in what they will eat
What might cause constipation in ASD patients?
ASD patients might engage in “faecal withholding”
changes in ENS function might parallel changes in CNS function
Are all mutations relevant to ENS?
no, some mutations might not present in the ENS and proteins that regulate spine morphogenesis may have alternative functions in the ENS
Why are neuroligins and neurexins relevant?
ASD-causing mutations in these genes would be expressed in ENS
mutations causing other neuropsychiatric diseases would also be expressed
Why is neuroligin 3 important?
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
What neurons do NL3 R451C mice have more of in comparison to their wild type litter mates?
more myenteric neurons and more nitric oxide synthase neurons in jejunum
Does ENS development differ between NL3 R451C mice and their wild type litter mates?
yes and this may be expected to have functional consequences
What are the consequences of altered ENS development in NL3 R451C mice?
small intestinal transit in vivo is accelerated in these mice
weight of caecum is reduced and associated with altered lymphoid tissue in caecum
Does the faecal microbiome in 5 week old NL3 R451C mice differ from wild type? What does this mean?
yes, this means that mutations in synaptic proteins that lead to ASD produce GI dysfunction
