Mechanisms of Neural Development
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What are the 5 stages of neural development?
• Neurogenesis • Migration + differentiation • Axon guidance • Synaptogenesis • Activity-dependent refinement
What is neurogenesis?
Creating the right number of nerve cells
The neural tube starts a single layer of replicating neuroepithelial cells. What are the two surfaces of this single layer?
• Plial (outer) surface • Luminal (ventricular) surface
How do neuroepithelial cells replicate to start with?
• Neuroepithelial cell drops down to luminal surface • Divides perpendicular to luminal surface • Forms another neuroepithelial cell next to original copy
Shortly after the neural tube has sealed, there are enough neuroepithelial cells - what happens next?
• Symmetric divison switches to asymmetric • Neuroepithelial cell drops down • Divides parrallel to lumen rather than perpendicular • Forms a neuroblast rather than another neuroepithelial cell • Neuroblast = newly developed nerve cell
What happens to patients with microcephaly?
They have small brains - due to loss of microcephalin protein, which is needed to produce sufficient nerve cells. Have severe learning difficulty, but specific neurological deficits are rare.
What is migration and differentiation?
Getting the cells to the right place
What do morphogens do?
Control what type of cells are produced
What directs neuroblast migration?
Chemical guidance signals eg. neuregulins, semaphorins
So how is the cerebral cortex developed (neuroblast, layers, direction)?
• The neuroblast migrates straight up to the pial surface • Marginal zone is formed (remains at pial surface) • Subplate is formed (moves down) • Both marginal and subplate act as directors/guidance • Extra layers are added underneath the marginal plate eg. cortical plate • This way cortical layers are created from inside to outside • Resulting laters = superficial, middle, deep
What is lissencephaly?
Loss of reelin, reelin is needed as a signal molecule, without it the cortex develops the wrong way (from outside to in) so cortex too thick. Leads to learning difficulties and epilepsy.
In axon guidance, what are the growth tips of neurites called?
Growth cones - carry receptors for chemical signals
What molecule is important for supporting filipodia (located in growth cones)?
Actin bundles
Describe what happens when the chemical guidance signals bind to the receptors in the growth cones
There are two different receptors: Attractive guidance - receptor that increases actin filament (growing) Repulsive guidance - receptor that shrinks actin filament This helps to grow the axon in a particular direction if both receptors are activated in different places / opposite ends.
What happens to people lacking key growth cone receptors?
Develop abnormal, ipsilateral sensory and motor pathways
Growth cones can only grow through tissues that they can stick to. How do filopodia bind to the extracellular matrix?
Extracellular matrix has matrix proteins - eg. laminin There are matching binding molecules on the growing filopodia - eg. integrin, which is a matching binding molecule. Integrin can then bind to laminin and grow through that particular area.
What is heterotopia and what causes it?
Caused by loss/mutation of doublecortin protein -> forms a double cortex, can lead to normal intellect to severe learning difficulties plus epilepsy.
Axons explore their target region by making ‘trial’ contacts with cells. What happens when a trial contact succeeds?
• Filipodia extend from dendrites, seeking contact from passing axons • Complementary surface proteins link and stabilise contact (eg. neuroligin-1 and B-neurexin) • Triggering formation of synaptic structures
Axons explore their target region by making ‘trial’ contacts with cells. What happens when a trial contact fails?
If surface molecules can’t bind to one another, the filopodium retracts (eg. 1a afferents and antagonist motor neurones)
What is activity dependent refinement?
Testing and perfecting the neural circuit
New synapses have few working glutamate receptors so are inefficient. Why is this?
• Activation of a single synapse will produce little effect • NMDA (gluR) receptor channels remain blocked by Mg2+ so don’t activate post-synaptic membrane • If this happens a lot, then the synapse is probably not doing anything useful
If many synapses activate simultaneously, what happens then?
-> Postsynaptic depolarisation -> NMDA receptors unblock and allow Ca2+ entry at active synapses
What synapse-strengthening processes does increased [Ca2+]in trigger?
• Inc number of AMPA receptors • Inc effectiveness of AMPA receptors (phosphorylation) • Inc size of dendritic spine • Inc size of axon bouton (via retrograde signals) Lead to an effective synapse, whilst those that aren’t acive at the same time as many others will shrink.
What is meant by synaptic plasticity in infants?
Each brain area/pathway has a unique “critical period” after birth, when it is still plastic so brains of babies can adapt to abnormal situations.