NEUR30004 Lecture Notes - Lecture 19: Knockout Mouse, Language Disorder, Spectrogram
11 Aug 2018
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Lecture 19
CAN THE MOUSE BE A MODEL OF HUMAN BRAIN DISEASE?
* In the last few decades there has been a huge advance in the way that we look at our genome. Our
genomes can now be sequenced at a lower cost and it makes it more feasible to have more subjects
in a study.
* On the other side, when you are dealing with a brain disorder you also want to have a look at what
it actually looks like in the clinic. So, we listen to clinicians who can describe behaviour, neurologists
do some testing to see if your motor reflexes are working and psychiatrists will observe behaviour
and sometimes prescribe drugs.
* People can also be put at the scanner, but the resolution is not good enough to look at the single
level of a neuron or even at circuits. So, this gap is bridged by using preclinical animal models. So, a
lot of our genomic data is telling us that complex brain disorders like schizophrenia and autism or
anything that has a psychiatric focus tends to be with circuits and synapses – so, a lot of the gene
mutations that are coming up tend to be in these areas. So, when preclinical models are brought to
the lab, what is of interest is to look at a particular genetic mutation and then put it into the genome
of a mouse and then seeing what happens – do we see the same things as in the clinic?
Are mice like us?
* There are some big differences between the mouse brain and the human brain – the mouse
brain have no wrinkles/sulcian gyri are absent in the mouse brain. Humans are able to put a lot
more brain tissue into their skulls due to having sulcian gyri, whereas mice are not the same, so of
ouse ie o’t hae the sae ehaiou, but there is a homologue for every human gene in the
mouse genome.
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Lecture 19
Is a mouse a little human?
* Homologue of every human gene in the mouse genome. “o, it’s ot eatl the sae, ut it ofte
has a similar function. So, this makes them really useful for us so that we can understand human
disease ad the geeti utatios e’e seeig oig fo the geoi side.
* Conserved function – similar cell functions, brain structures and behaviour. So, maybe these genes
have similar functions or similar brain structures in mice and maybe we can then take that jump and
say that they have similar behaviours. But, we have to be careful because a mouse is not necessarily
a little human.
* We can genetically modify mice and control their environment. These cannot be done in humans
at this point in time.
* So ie are’t little huas, ut the are a good pro.
The embryo:
* An embryo – every single cell in an embryo can be a different cell type. But, every single cell in the
embryo starts off with the same genetic code.
Focusing on neurons:
* Ou DNA is like a luepit ad e do’t at to take it out of the ahitet’s offie eause we
might destroy it, and destroying it is particularly bad. Instead we take a photocopy and then our
building blocks will read that photocopy to put them together to make a structure. So, the house is a
metaphor for the protein.
*This is transcription & translation and this is one of the reasons why we end up with a neuron.
What switches on these genes if we have the same genetic code for every single embryonic cell,
what changes which DNA is relevant for that particular cell type?
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Lecture 19
*We’e all orn with a genetic code, but what makes us different?
Thik of ou geeti ode as a dek of ads. “o, he ou’e dealt a had of ad, ho do ou pla
them? So, you could be really lucky and have a fantastic deck of cards or you could be unlucky, but if
you have a fantastic poker face you might compensate for any of the genetic mutations you might
have. All of us hae geeti utatios, it’s hat akes us idiiduals – it’s a e oo thig i
our genome.
What happens when these genetic mutations actually become a liability?
* Autism - Affects young children mainly boys, leads to obsessive behaviour and sensory overload.
What does Autism Spectrum Disorder look like in people?
* Autism spectrum disorder runs in families.
* Is it in the genes? There are so many genetic mutations in patients with
Autism. It is not known whether there is a single mutation for autism. In
very rare cases, very penetrant genetic mutations which means that if
you have this mutation, you have a very good chance of developing
autism. But, in the majority of cases, it is hard to determine how many
different types of these mutations you need before you have the actual
disorder.
Using mice to understand genetic disorders?
* All of the proteins with red text in the picture below have been implicated to autism in one way or
the other. Some more strongly than others. Note: that there are quite a few in the complex to the
left that’s idgig the sapse.
* Neuroligin 3 is a key post-synaptic scaffolding protein that binds to neurexin. Neuroligin 3 &
eurei are reall iportat, the’re iportat for deelopet, ut the’re also iportat for
plasticity.
* What happens if we find a patient specific mutation such as the R451C mutation which is an
arginine to cysteine substitution that has been found in 2 boys – so a lot of people say how is that
relevant to autism if the incidence rate is so low? But, many mutations have been found in SHANK,
many in neurexins and the associated proteins. “o, the theo is that e’e found a rare mutation
that’s highl peetat so it’s e likel that if ou hae this utatio the ou ill deelop autis,
ut it’s ot e oo, ut it ight e a good ase stud fo udestadig ho autis atuall
change synapses and changes circuits and then leads to changes in behaviour.
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find more resources at oneclass.com
Document Summary
* in the last few decades there has been a huge advance in the way that we look at our genome. Our genomes can now be sequenced at a lower cost and it makes it more feasible to have more subjects in a study. * on the other side, when you are dealing with a brain disorder you also want to have a look at what it actually looks like in the clinic. So, we listen to clinicians who can describe behaviour, neurologists do some testing to see if your motor reflexes are working and psychiatrists will observe behaviour and sometimes prescribe drugs. * people can also be put at the scanner, but the resolution is not good enough to look at the single level of a neuron or even at circuits. So, this gap is bridged by using preclinical animal models.
