Neurological disorders

Question 1

What occurs when there are mutations in the L1 commissural axon?

Answer 1

• ‘CRASH’ syndrome
• spastic paraplegia, hydrocephalus etc.
• characterised by defects in axon pathfinding at the pyramidal decussation of the cortical spinal tract
• spastic paraplegia is due to failure of the CST to project beyond cervical regions
• direct effect mutation –> phenotype

Question 2

What is horizontal gaze palsy caused by?

Answer 2

• due to mutation in Robo3
• affects several commissures , crossed fibre tracts in the pons coordinate eye movements
• understood why these individuals then get scoliosis, lack of eye coordination maybe?
• direct effect mutation –> phenotype

Question 3

What is Kalmann’s syndrome and what is it caused by?

Answer 3

A condition where GnRH neurons fail to migrate to the hypothalamus, hindering gonad development.
Causes:
- Linked to mutations in genes like Sema3A and Sema7A.
- Sema3A: Needed for olfactory epithelial axon guidance; without it, axons don’t reach the olfactory bulb, misdirecting GnRH neuron migration.
- Sema7A: Mutations result in no migration of GnRH neurons.

‘indirect effects’

Question 4

How is autism an indirect neurological disorder?

Answer 4

• Clear genetic components but very complex
  Each factor has a less than 1% risk, multiple factors usually seen at once
• Mutations in genes that effect: synapse formation, Wnt signalling, regulatory processes, cell migration etc etc. SO many!
• Quite a lot of overlap

Question 5

What is genetic redundancy and how is it relevant in neurological disorders?

Answer 5

• Pathways taking a KO’s place (45-65% of mouse genes knocked out are viable and fertile (ie ‘non-essential’))
• Mice and humans can survive well with many genetic and neurodevelopmental disturbances
• May underlie the wide variety of personalities
• This variation is vulnerable to environment (e.g. cannabis → schizophrenia)

Question 6

What happens if systems are too robust?

Answer 6

• variability is not expressed which is disadvantageous in changing environments
• we have to be variable to have to adapt to different environments, switching between scenarios
  E.g. mice using directed behaviour to find food in a known environment but using exploratory behaviours to find food in an unknown environment

Question 7

When are different type of behaviours advantageous?

Answer 7

1. Known environment = directed behaviour wins; favours robust, unaltering system
2. Unknown environment = exploratory behaviour wins; favours system able to vary in response to change

Question 8

What is the ‘Turn bias’ in flies - Locomotor studies?

Answer 8

Automated analysis of turning behaviour of large numbers of flies in Y maze array
- Do they turn left or right is variable amongst the flies despite having the exact same genotype

Question 9

In alterations of the locomotor studies, what did varied strains show?

Answer 9

• distinct fly strains showed different levels of variability in the behaviour e.g. fly strain A showed little variability in turn bias scores
• behaviour is variable but the amount of variability is determined by the genetics
• using genome sequencing they found the genes important in variability’ are genes important in neurodevelopment

Question 10

What are the critical points from the locomotor studies?

Answer 10

• the genetics is controlling the range of the variability of the turn bias scores in the population, not whether a specific TBS is present in any particular individual
• for a particular individual, their turn bias score is persistent over time, suggesting it is a function of their individual circuit connectivity.

Question 11

What are the three contributors to phenotypic variability?

Answer 11

• Specific brain regions set up to introduce variability into behaviour
• Environmental insults
• Random events during development

Question 12

What is the variability between brains of monozygotic twins?

Answer 12

• Morphological variability of the sulci and gyri
• Axonal variability

Question 13

How does monozygotic brain variability arise?

Answer 13

• Random differences in connectivity underly behavioural ‘personalities’
• IN flies, individuals can be classifies as narrow or broad path walkers- persisting throughout its life
• Dorsal cluster neurons projecting into the rest of the brain varies between individuals
• When silencing these DCNs, it turns all flies into broad-path walkers
• Asymmetry = narrow, symmetry= broad

Question 14

What determines where DCN project to?

Answer 14

• notch/delta interactions during axon targeting
• whether notch is on/off is determined by lateral inhibition
• unpredictable between flies
• neurons in which notch is ON innervate the lobula
• neurons in which notch is OFF innervate the medulla
• this controls the ‘walk’

Question 15

How do genotype and environment interact to influence disease manifestation?

Answer 15

Genotype’s Role:
Genotype 1 has a broader range of phenotypes, including extreme ones above the threshold that lead to disease.
Genotype 2 has a narrower range, typically below the disease threshold.

Environmental Influence:
- Environmental insults can push phenotypes just below the disease threshold into the disease state.
- Individuals with Genotype 1 are more likely to be affected by such insults than those with Genotype 2.
- Example: Cannabis may trigger schizophrenia only in genetically predisposed individuals.