L26 - Neuropsychiatric diseases Flashcards
What studies have been done showing that many neuropsychiatric diseases are genetic disorders?
•Twin studies show a high degree of concordance (similarity) between monozygotic twins
–ASD (also 4:1 male: female gender ratio)–Schizophrenia (no gender preference)
–ADHD –X-linked intellectual disability
List two ways to study genetic basis of disease
1) GWAS (Genome wide association studies) – obtain as any patients with the disorder and map their genomes to look for trends. Tends to miss rare, high impact, mutations (many genetic mutations affect only a small number of individuals)
2) Exome sequencing of parents, affected patients (probands) and unaffected siblings
- Works best if have the full triad
- Can identify copy number variations (CNVs), SNPs, within gene deletions
- This fails to understand the regulatory mechanisms that might be modified as well e.g. Herschbrung’s disease appears to be due to an upstream regulatory component of the genome that does not affect the genome at all, but rather is in an inter-gene space, several hundred nucleotides away from the gene that is ultimately effected.
Proteins mutated in ASDS are all synaptic proteins (the proteins in between synapses) + SHANK protein
Proteins mutated in ASDS are all synaptic proteins (the proteins in between synapses) + SHANK protein
PPI - in which 4 disorders?
PPI networks of all 4 disorders (ASD, Schizophrenia, ADHD, X-linked intellectual disability) showing primary candidate genes and their adjacent neighbours
-The mutation for ASD and Schizophrenia is the same, indicating both presence of genetic (susceptibility factors) and environmental effect
Up to _% of ASD patients reported to have gastrointestinal dysfunction, notably constipation
90
Not all mutations in ASD are relevant to ENS
Most of the mutations in autism to do with synapses are in dendritic spines, whereas dendrities of enteric neurons are short and mostly lack spines. ASD mutation in neurolign 4 occurs in the retina.
•The relevance of the mutation to the ENS lies in the development of neural cells.
–Brain neurons are derived from neural tube VS Enteric neurons are derived from neural crest
ASD-causing mutations in ____ and ____ would be expressed in ENS
Neuroligins 1-3 and neurexin 1 & 2–In myenteric plexus (MP) and mucosa (M)
•Mutations causing other neuropsychiatric diseases would also be expressed
Why is neuroligin 3 important in ASD?
•Two mutations in neuroligin 3 produce ASDs
–Gene deletion, CNV (copy number variation) (1 patient)
–Point mutation that substitutes cysteine for arginine at position 451 in protein
•2 brothers in Sweden (one severe ASD, one with Asperger’s) – both with GI problems
•NL3R451C mice increased GABA function in sensory cortex, increased glutamate function in hippocampus and mimics the KO at some GABA synapses & had some ASD behaviour
The NL3R451C mouse as a model - what 3 validities are required?
•Construct validity- show that animal has right basic biology to match human disease
-can insert human gene into mouse
•Face validity - behaviours induced by mutation have to match what you see in the human patient
–NL3R451C mouse shows several behaviours considered characteristic of ASD including aggression, stereotyped behaviour and abnormal communication
•Predictive validity - a treatment that work in the mouse will work in the human
–Aggression in NL3R451C mouse restored to normal by respiridone (atypical antipsychotic), treats
NL3R451C mice have more/less myenteric neurons and more/less nitric oxide synthase neurons in jejunum? The functional consequence of increase NO synthase is?
More, more
Nitric oxide synthase - makes NO -> Inhibitory NT of smooth muscle*also changes neural muscular transmission
GABA has excitatory function in ENS. Increase/decrease in Colonic Migrating Motor Complex when GABA A blocker (bicuculline) is present hence either GABA function or susceptibility to GABA has been increased/decreased
Decrease, increased
Colonic function is altered in NL3R451C mice, but need to perturb the system (block GABA function) to see the disturbance (don’t see change at baseline)- it’s not that ASD patients have more GI problems at baseline, it’s that they have a worse GI problem when they do get it
Colonic function is altered in NL3R451C mice, but need to perturb the system (block GABA function) to see the disturbance (don’t see change at baseline)- it’s not that ASD patients have more GI problems at baseline, it’s that they have a worse GI problem when they do get it
