mechanisms of neural development

Question 1

How does the nervous system achieve its complex wiring?

Answer 1

• neurogenesis (creating right number of cells)
• migrations and differentiation (getting cells to the right place)
• axon guidance (growing an axon to the right target area)
• synaptogenesis (making connections with potentially useful partners)
• activity-dependent refinement (testing and perfecting the neural circuit)

Question 2

Neurulation

Answer 2

• inner surface is luminal surface, which eventually turns into the ventricles
• the outside becomes the outside of the brain - pial surface
• made of a single layer of neuroepithelial cells

Question 3

Neuroepithelial cells

Answer 3

• long thin cells - become radial glial cells later in development
• these are the progenitors for nerves and glial cells
• every so often they will release their hold on the pial surface, drop down to the luminal surface and will divide
• early on in development they divide perpendicular to the surface - daughter cells become neuroepithelial cells and part of the structure
• neural tube is gaining surface area, but so far we arent producing nerve cells

Question 4

Neuroepithelial cells to neurones and glia

Answer 4

• once the SA gets big enough, some will drop down but divide parallel to the surface
• these contain IC messengers and are polar - contact with the luminal surface means that they produce different messengers at this end
• if they divide perpendicularly they will always form neuroepithelial cells
• if they divide parallel, then the cell born furthers from the lumen will do something completely different - switch on different sets of genes and become neuroblasts

Question 5

Mutations in the control of neuroepithelial cell division affect brain size

Answer 5

• Mutation in microcephaly protein leads to the loss of microcephalin
• causes person to have a small head and brain with severe learning difficulties
• havent produced sufficient numbers of divisions and therefore nerve cells
• macrocephaly is also possible
• develops normally but doesnt have enough machinery inside

Question 6

Early development of the cerebral cortex

Answer 6

• neuroblasts reach up along process, grab onto the radial glial cells, pull themselves up and then repeat
• the nerve cells at first are very motile, they slowly crawl off onto the right place

Question 7

What do Morphogens do?

Answer 7

• all along the surface of the lumen cells are growing
• what cells these become, what genes these become, determining their future and behaviour - depends on morphogenic signals
• Bone morphogenic proteins are produced in the dorsal area
• SHH is produced ventrally
• there are gradients for morphogens stretching across the brain, medial to lateral, front to back
• these morphogens will switch on the right genes in order to get them to become the right cells and to migrate to the right place

Question 8

What are chemical guidance signals?

Answer 8

• tell the cells where they are supposed to go
• there are conc gradients for a variety of different guidance signals
• cells that are born at the cerebral cortex switch on genes, making them sensitive to Reelin - produced right on the pial surface, and so head straight to the top
• some born in the ganglionic eminence have genes switched on telling them that they are going to be an inhibitory neuron in the ccx - even though they are born so far away
• combination of genes switched on due to morphogens and guidance chemicals tell the cell where to go when migrating

Question 9

Neuroblasts migrate towards the pia mater

Answer 9

• Neuroblast climbs up to pial surface where it will take residence
• first cells to arrive are marginal zone cells
• the next ones come up and settle behind. These are called subplate cells
• The next wave move up and push through the subplate to be as close to the marginal zone as possible
• after this, each wave does the same thing, so the cortex is assembled inside out

Question 10

Cortical layers are created inside out

Answer 10

• as the waves of cells arrive, the morphogens are changing within the area that they are being born
• successive waves have different genes being switched on which will tell them to behave in different ways
• cells are being laid down in layers, with each successive layer having a different function

Question 11

What layers do what?

Answer 11

• first ones to arrive are deep layers (layers 5 and 6)
  > excitatory ones are bid pyramidal cells that have long axons that go deep down to subcortical structures
  > will project back down to thalamus and brainstem. (motor cortex they project down whole spinal cord as corticospinal tract)
• middle layer (layer 4)
  > turn into stellate cells
  > receptive cells of the cortex - receive inputs from cortical areas such as thalamus
• superficial layers (2 and 3)
  > turn into small pyramidal cells that have projections to layer 4 in other cortical areas

Question 12

What other cells are produced?

Answer 12

• inhibitory interneurons are born in ganglionic eminence and migrate here
• once all the nerve cells you need have been produced, neuroepithelial cells start to produce glial cells
• astrocytes come from local neuroepithelial cells
• oligodendrocytes are produced in ganglionic eminence
• very complex pattern of migration
• when all are in place there are very few stem cells left
• subplate cells act to help direct the outgrowth and ingrowth of axons to the cortex
• about 4-6 weeks before both, marginal and subplate cells disappear - mature cortex

Question 13

Mutations affecting migration signals disrupt cortical organisation

Answer 13

• migration signals are essential
• reelin calls the cells below up to the cortical plate - if no reelin, cortex develops the wrong way round and it wont wire itself up correctly
• MRI shows that the cortex is way too thicl - not enough SA or infolding - gives severe learning difficulty and most likely epilepsy

Question 14

Axon guidance

Answer 14

• growth tips of neurites are called growth cones - actin filaments push membrane of filapodia out
• carry guidance signals
• depending on whether there are attractive guidance signals (actin bundles grow) or repulsive guidance signals (actin bundles shrink)

Question 15

Growth cones can swap receptor at specific locations

Answer 15

• axons don’t grow in a straight line, they will have to go through complex routes sometimes
• e.g. neuron in dorsal horn of spinal cord
• axon has to go around the lumen and up the contralateral side
• when it is developed, receptors are produced that mean that it is attracted towards the floor plate to go around the lumen
• when the axon touches the floor plate, the gene expression is altered and the attractive receptors are replaced with repulsive ones - causes axon to grow away from the floor plate, out laterally and turn up towards the brainstem
• they grow via a set of waypoints where they change expressed receptors and change direction
• some people lack receptors that cause the axon to go towards the floor plate and just grow straight up on the same side

Question 16

Growth cones can only grow through tissues that they can stick to

Answer 16

• ECM in the brain expresses different matrix proteins in different areas
• e.g. laminin - the growth cones can only extend through the tissues that they can stick to
• if a growing filopodium expresses integrin, it can stick down and grow across the areas that have laminin - however if it doesnt have integrin, it wont be able to grow through the laminin and has to find a route around those particular areas - they need traction to extend and grow

Question 17

Mutations affecting the cytoskeleton disrupt cortical development

Answer 17

• cells need to migrate in the right direction so need the right guidance signals
• A mutation in the doublecortin protein leads to a double cortex - heterotopia
• Depending on how many cells express the mutant protein, some of the cells will go to the cortex and some will go to the second cortex underneath
• Girl would have 2 X, so likelihood of cells being on the wrong cortex is 50%
• depending on how many cells go to the right place, very likely to have learning disabilities and epilepsy as there won’t be correct wiring
• boy with same prob will have no correct protein - very severe

Question 18

How do cells make new synapses?

Answer 18

• filopodia extend from dendrites - seek contact from passing axons
• complementary surface proteins link and stabilise the contact (e.g. neuroligin-1 and b-neurexin)
• trigger formation of synaptic structures

Question 19

What happens if the cells cant make new synapses?

Answer 19

• if surface molecules cant bind to one another, the filopodium retracts
• e.g. 1a afferents from muscle spindles and antagonist motor neurones

Question 20

How do neurones determine which synapses to keep?

Answer 20

• NMDA receptor is glutamate receptor that opens a channel when binding occurs.
• however this channel is blocked by a magnesium ion, so just binding glutamate has no effect - need synaptic membrane to depolarise
• If the synapse is part of a useful circuit, lots of receptors will be activated at the same time - good chance that working together will reach the potential and depolarise membrane enough
• if so, NMDA receptor will lose its Mg ion and Ca will enter - triggers lots of responses
• Calcium can cause an increase in number of AMPA receptors and increase effectiveness through phophorylation
• causes bouton to grow bigger and release more glutamate - more effective synapse
• those that are not active all at once and cannot remove the mg block will shrink away.

Question 21

Why is there a critical period?

Answer 21

• Synaptic plasticity decreases during development
• very effective in foetus (weak inhibition and super-effective NMDA channels)
• it is still high in babies allowing their brains to adapt to abnormal situations
• many pathways become fixed and stable during childhood
• each brain area has a unique critical period where it is still plastic

Question 22

What does high plasticity in early life allow?

Answer 22

• brains can adapt to abnormal situations
• those with ipsilateral sensory and motor pathways have almost normal function
• ## children who suffer severe brain injury can recover most function - e.g. child lost half cerebral cortex but other half compensate and control both sides