Lecture 28- Neuropsychiatry and gut Flashcards
What are some of the neuropsychiatric diseases?
- Schizophrenia • Depression • Bipolar disorder
- Autism, autism spectrum disorder • Attention deficit hyperactivity disorder
- Obsessive compulsive disorder • Tourette’s syndrome
- X-linked intellectual disability • Alzheimer’s dementia • ?Parkinson’s disease
- major issue in the world
- getting a psychotic episode is a side effect of taking marijuana autism usually diagnosed 0.5 to 1.5 years of age
- Tourette’s syndromes= ticks, involuntary behaviour,
Are many neuropsychiatric disorder genetic?
- yes -great majority of neuropsychiatric patients have a genetoc component to it, why would the mutations in the brain not affect the ENS since it is a big nervous system
- it has a genetic component since twin studies show high degree of concordance
- autism= so much more common in males, must be genetic
- ADHD= twins have it, mostly male problem
- X linked= has to be genetic, gene involved is on the X chromosome so mostly in males
• Twin studies show a high degree of concordance between monozygotic twins:
– ASD (also 4:1 male:female gender ratio) – Schizophrenia (no gender preference) – ADHD – X-linked intellectual disability (obviously) – Etc
• Significant environmental component determines penetrance and severity
What are the two key tools for study of genetic basis of disease?
- Genome wide association studies (GWAS)
- Exome sequencing of parents, affected patients (probands) and unaffected siblings
What are genome wide association studies (GWAS)?
– Tends to miss rare, high impact, mutations
• Many genetic mutations affect only a small number of individuals
—GWAS= method to compare large numbers of people, common in diseased people (work really well when just one or few genes that affect the disorder), but miss situation where high impact on individual and not widely had
What is exome sequencing of parents, affected patients (probands) and unaffected siblings?
– Works best if have the full triad
– Can identify copy number variations (CNVs), single nucleotide polymorphisms (SNPs), within gene deletions
- sequence parents, sufferer (proband) and unaffeceted sibling, here looking for the mutations that cause the disorder
- here can identify rare mutation
What are some of the proteins mutated in ASD?
- some are synaptic proteins (in red)
- 30% of mutations now identified are responsible for ADS, accounts for 25% of patients
- neurolignin and neurexin
- cross membrane binding proteins
- eg. CNTNAP2 associated with language delays( big part of autism)
- some of the proteins that have been identified by the exome sequencing
- but it doesn’t tell you the range of people and exactly what it does
What do protein-protein interactions show in the diseases?
- Protein-protein interactions show strong overlap between diseases do the proteins interact with one another (the ones that are identified as common in the disorders)
- genes for fours diseases, many of the genes involved are in common, one gene that is common 21 is common to schizophrenia and autism
- not just gene but the mutation= schizophrenic father to autistic son, different outcome in each
- which protein target is theirs, first order interaction= then even bigger overlap, then 127 proteins that are common to each
- Details of diagrams (c) “PPI networks of all 4 disorders showing primary candidate genes and their adjacent neighbours” AXAS-PPI shows the amalgamated network with genes that overlap more than one disorder being black
What are the functional interactions of the proteins involved in the diseases?
-Protein-protein interactions converge on synaptic proteins and neurodevelopment
- Major pathways include the neurexin-neuroligin-Shank axis – ASDs – ?Schizophrenia?
- Other work implicates neurexin 1, neuroligins 1, 3, 4 and Shank 2 and Shank 3
- Many mutations involved in these proteins -clusters of M2= synaptic proetins and regulation and synaptic function
- proteins of synaptic function are often associated with these disorders
- neroxin and shank axis= the stabilization of the synapse, and the synaptic density
- Each gene cluster produces proteins with related functions
Is ADS associated with gut issues? If so how?
ASDs are associated with gut problems
- Up to 90% of autism patients are reported to have gastrointestinal dysfunction, notably constipation
- ASD patients are often very selective in what they will eat – Highly restricted diets complicate interpretation of gut issues
- Explanations are varied, but there is no literature on involvement of the enteric nervous system -someone with autism 4x as likely to have constipation
- 2/3 of people don’t communicate
- first explanation= due to brain disfunction,= gut disfunction= fecal retention= the individual finds defecating embarrassing, uncomfortable, they refuse to do it
Are all the mutations relevant to the ENS?
-Not all mutations may be relevant to the ENS Dendrites of enteric neurons are short and mostly lack spines
- Do proteins that regulate spine morphogenesis have alternative functions in the ENS?
- Are they even present in the ENS? – Brain neurons are derived from neural tube – Enteric neurons are derived from neural crest
- do ENS neurons have dendritic spines, are the genes in CNS in the ENS?
- we assume it would but they have different embryologic origins so the genes can be very different
Are neuroligins and neurexins relevant, how?
- RT-PCR showing expression of mRNA for neuroligins 1-3 and neurexin 1 & 2 – In myenteric plexus (MP) and mucosa (M)
- ASD-causing mutations in these genes would be expressed in ENS
- Mutations causing other neuropsychiatric diseases would also be expressed
- colon mucosa, myenteric plexus and duodenum mp, and duo m,
- shows some of the genes are indeed expressed in the gut, cannot tell exactly where
Why is neuroligin 3 important?
• Two mutations in neuroligin 3 produce autism :
– Gene deletion (1 patient)
– Point mutation that substitutes a cysteine for a arginine at position 451 in protein
- 2 brothers in Sweden – both have GI problems
- NL3R451C mice – some autistic behaviours
- NL3R451C mice increased GABA function in sensory cortex, increased glutamate function in hippocampus and mimics the KO at some GABA synapses
- have a mouse that has mutation in it that causes autism
- two types of mutation
- NLR3 R451C (neurolignin 3 mutation)
- bad gastrointestinal symptom
- then mice had this gene put into them and produce some autistic behaviours
- weird GABA functions
How can you use the NLR3 R451C mouse as a model?
- Construct validity – The mouse gene for neuroligin 3 has been replaced with a human gene with the Arg451 replaced by Cys – Human gene caused autism in two brothers
- Face validity – NL3R451C mouse shows several behaviours considered characteristic of autism including aggression, olfactory deficits and abnormal communication
- Predictive validity – Aggression in NL3R451C mouse is restored to normal by respiridone (atypical antipsychotic), which is used to treat aggression in autistic patients
-need to make sure that all this is true: -these things to make sure the mouse is a good model for this particular type of autism
What is the research question considered?
-Do NL3 mice have abnormal gastrointestinal function?
- The development of the ENS differs between NL3R451C mice and their wild type littermates
- This may be expected to have functional consequences
- Colonic function is altered in NL3 mice, but need to perturb the system to see the disturbance
- As all connections to the central nervous system are absent in vitro, dysfunction must be due to an altered enteric nervous system
- MUTATIONS IN SYNAPTIC PROTEINS THAT LEAD TO AUTISM CAN PRODUCE GI DYSFUNCTION INDEPENDENT OF ANY BEHAVIOURAL CHANGES
