Lecture 33- Developmental disorders I

Question 1

What are the stages of neural development? (9)

Answer 1

1. Neural induction 2. Neurulation 3. Morphogenesis and patterning of the neural tube 4. Neurogenesis 5. Neuronal migration 6. Axon guidance 7. Neural crest 8. Synaptogenesis 9. Glia development

Question 2

How common are perturbations in neurulation?

Answer 2

-neural tube defects occur in 0.1-0.2% of pregnancies -second most common congenital defect -neural tube remains open at some point along rostro-caudal axis due to: failure of neural fold elevation or failure of closure

Question 3

What happens when there is a disruption of proliferation/migration? (pyramidal neurons)

Answer 3

-heterotopias are formed when neurons fail to migrate from the ventricle, or migrate halfway towards the cortical plate -displays as unorganized islands of neurons -normally ventricular surface is smooth, here nodules= heterotopias= the neurons don’t migrate away from the ventricle

Question 4

What is a periventricular heterotopia?

Answer 4

-when the heterotopia is lining the ventricle -more specific name

Question 5

What is the cobblestone cortex?

Answer 5

-arises when neurons over-shoot the cortical plate and reside in layer I -when migrate on the other side and form bubbles on the outside

Question 6

What happens in normal cortical development?

Answer 6

• progenitor pool and expansion and neurogenesis
• neuronal migration
• cortical lamination

Question 7

What can happen to the cortical layers if there are migration defects?

Answer 7

• reduced progenitor proliferation, early neurogenesis= reduced neuronal number
• disrupted migration= thick dysplastic cortex, abnormal lamination

Question 8

What can happen to cortical layers if there is a glial fiber defect?

Answer 8

-disrupted basal lamina, mis-oriented radia glia= cortical dysplasia, overmigration

Question 9

What are the transition points in radial migration (pyramidal neurons)?

Answer 9

• progenitors proliferate, attachment of radial fiber
• glial dependent migration
• transition to multipolar morphology
• bipolar morphology
• detachment and termination of migration

Question 10

What are the genes involved in the transition points in radial migration (pyramidal neurons)?

Answer 10

• Filamin A
• LIS1
• FILIP
• DCX (doublecortex)
• DCX overexpression

=these cause migration defects

Question 11

Can migration disruption occur when there is a disruption in the factors regulating migration?

Answer 11

-yes -e.g. Reelin

Question 12

How can mutations in the genes that cause brain abnormalities occur?

Answer 12

1. inherited mutations from either parent:
   - heterozygous mutation is inherited from one parent and all cells from the zygote phase will carry the mutation, this is typical for autosomal dominant epilepsy
   - de novo mutations arising sporadically during gametogenesis
2. early or late post-zygotic mutations:
   - early post-zygotic mutation results in a mutation present in all tissue but in a mosaic fashion, an example is double cortex syndrome
   - a late post-zygotic mutation results in a mutation in only certain tissue in a mosaic fashion, example is hemimegalencephaly (HMG) with the AKT3 mutation

Question 13

What mutations are often associated with malformations in cortical development (MCD)?

Answer 13

• genetic studies have identified several genes associated with malformation s in MCDs that disrupt proliferation and specification, migration and cortical organization
• proliferation: a) focal cortical dysplasia b) enlarged hemisphere
• migration: c) LIS1 mutation d) LIS1 mutation e) LIS1 and DCX mutation f) DCX mutation g) Arx mutation h) Reeling mutation

Question 14

Why is the balance of inhibitory inerneurons and excitatory pyramidal neurons important?

Answer 14

-the neocortical excitation/inhibition balance is important, if don’t get it right can result in severe behavioural deficits such as autism, schizophrenia -these were hypothesized to arise as a result of imbalance between excitation and inhibition within neural circuits -can see if true using optogenetics= mostly true

Question 15

How are brain disorders connected to developmental defects in interneurons?

Answer 15

-interneuron dysfunction is associated with neuropsychiatric disorders such as schizophrenia, epilepsy, autism and anxiety disorders -reduced number of interneurons in human postmortem specimens of patients with these disorders supports this -Neuregulin and ErbB4 are susceptibility genes for developing schizophrenia, both genes are involved in interneuron migration during development

Question 16

How is epilepsy a neurodevelopmental disorder?

Answer 16

• epilepsy is characterised by spontaneous recurrent seizures and comprises a diverse group of syndromes
• the timeline shows genes that when disrupted can result in epileptegenesis
• decrease in interneurons

Question 17

What do schizophrenia patients often exhibit? (GABA wise)

Answer 17

-loss of some GABA cortical circuits -alterations in pre and post synaptic markers of GABA neurotransmission in the dorsal lateral prefrontal cortex of subjects with schizophrenia (some layers more susceptible than others -lamina specific or subtype specific loss in schizophrenia) -protracted maturation of interneurons (problems can emerge later in life)

Question 18

What is the two hit hypothesis for schizophrenia?

Answer 18

• hit 1: developmental diruption: issue in the brain, creates a susceptible brain
• hit 2: acts on the susceptible brain and causes a disease/mental issue

Question 19

What are the developmental links between Neuregulin-1 and schizophrenia?

Answer 19

-Neuregulin-1 and the receptor ErbB4 are promising genetic susceptibility factors in schizophrenia (DISC1) -NRG acts as a chemoattractant for the tangential migration of interneurons from the ganglionic eminence into the cortex

Question 20

What is the interaction between neuregulin signalling and interneuron function?

Answer 20

-a conditional knockout of ERbB4 from the two classes of fast spiking interneurons -boost cortical excitability, increase oscillatory activity and disrupt synchrony across cortical regions -these functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behaviour and cognitive function

Question 21

What is the wiring of the adult brain like?

Answer 21

• occurs during embryonic and postnatal development
• commissural and longitudinal projections in the forebrain
• A) corpus callosum, hippocampal commisure

B) anterior commisure

C) optic chiasm

D) longitudinal tracts include the corticothalamic, thalamocortical and corticospinal tract

Question 22

What are the axons guidance defects in the corpus callosum and the effects of this?

Answer 22

-agenesis of the corpus callosum is a birth defect that is associated with mental retardation and sensory and motor deficits where children fail to learn to talk and walk -severity is dependent on whether nervous system wiring deficits are present

Question 23

How long does it take for a brain to finish myelination (humans)?

Answer 23

-approx. 21 years (reason for drinking age in the US)

Question 24

How can social isolation affect brain development?

Answer 24

-global neglect and brain development: -the brain is smaller, less myelinated

Question 25

What is the interaction of social experience and oligodendrocyte development?

Answer 25

-juvenile social isolation and neglect influence adult cognitive function and social interactions , this correlates with alternations in white matter tracts associated with medial prefrontal cortex -in a mouse model of social isolation there is a reduction of white matter which can be recapitulated by reduced expression of ErbB3 receptors and the ligand Neuregulin-1

Question 26

Summary slide:

Answer 26

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