Mechanisms of Neural development
Neurogenesis
Def
Nervous system complexity
Each neurone follows a unique development plan mincing a uniques set if connections at unique locations: - Each neurone has different dendrites, receptor and NTs 
Creating the right number of nerve cells
Migration & differentiation
Def:
Getting the right cells to the right place
Axon guidance
Def:
Growing an axon to the right target area
Activity dependant refinement
Def
Activity dependant refinement - testing and perfecting neural circuits
The origin of neural tissue
origin: from ectoderm trigeminal germ disc
how? via the process of neuralation
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Neuroepithilal cells
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Neuralation
- ectoderm infolds then breaks away from neural tube
- at this point the neural tube is a group of long thin cells that have a pial surface (forms the outside of the brain) and luminal surface (forms the surface of the ventricles)
- Eventually this group of cells (neuroepithelial cells) proliferate and grow closing the neural tube
Background
• Nomenclature: The neural epithelial cells are also known as radial glial cells
• Location: span the neural tube from pial cells at the top to the luminal cells at the bottom
• Purpose: they divide and proliferate in order to expand the neural tube
• MOA when neural tube is open:
1.they drop from the pial surface all the way to the luminal surface where they divide at the bottom perpendicular to the luminal surface.
2.Both the daughter cells then rise and reconnect with the pial cell surface, as they do so they expand the neural tube
Clinical significance
Rule: Certain mutations can cause neuroepithelial cells to:
Divide too much leading to an excessively large brain size (macrocephaly)Divide too little leading to an excessively small brain size (microcephaly)
Once neural tube is closed MOA:
daughter cells are still produced from neuroepithelial cellsexcept that when they drop to drop from the pial surface all the way to the luminal surface where they divide at the bottom parallel to the luminal surfaceThe significance of this is that if the cell divides perpendicular to the luminal surface both daughter cells will receive a mix of this substance called morphogens that tell them to remain neuroepithelial cellsBUT if the cell divides in the parallel plane. The top cell contains a particular mix of morphogens which tell it to attach to another neuroepithelial cell instead of the pial surfaceThis forms a neuroblast
Rule:
as soon as neural tube is closed neuroblasts begin to be born
Context
Let’s start where we left off from the new-born nerve cell (neuroblast):
Rule:
• Neuroblasts move away from their place of birth
Morphogens
Purpose: tell cells being born in different locations around the brain what genes to switch on/off and so what type of cells they become and where to go
MOA:
1.Particular morphogens switch on genes that transcribe the insertion of receptors in the outer membrane of these neuroblasts to tell them where to go.
2.These receptors detect the guidance morphogens that they have been programmed to follow depending on their location. Once in the correct location these nerve cells can then differentiate
-Cerebral hemispheres - The green cells born at the top in the cerebral hemispheres will migrate upwards towards the guidance morphogen of the area – Reelin. These cells form excitatory neurones
-Basal Ganglia – Some cells (yellow) will migrate towards the basal ganglia and others (black) will become attracted to the reelin and migrate upwards towards the cerebral hemispheres where they form inhibitor neurons
Example: Neuronal cell of the cerebral cortex
A neuronal cell of the cerebral cortex has several things programmed at birth
a) It will become an excitatory neuron
b) It will be attracted to reelin
Development of the cerebral cortex
Continuing on with this example:
MOA:
1.Reelin is found underneath the pia cells so these excitatory neurons thus form a layer underneath the pia mater.
2.The first layer of cells are called subplate cells – subplate cells don’t live very long and act as trafficking cells providing guidance signals to help the rest of the nerve cell find their way
3.The second lot of neuronal cells born migrate towards the reelin passing the subplate cells – this second layer of cells are called cortical plate cells
4.Overtime – the cortex develops with multiple layers of these cortical plate cells developing ordered from youngest to oldest (top to bottom).
5.Once a sufficient number of cortical layers have been laid the different layers of cortical plate cells begin to differentiate.
-The oldest cells (deepest layers) form pyramidal cells which develop into subcortical structures
-The middle layers form stellate cells which receive subcortical and cortical inputs
-The superficial layers form superficial pyramidal cells that send their axons to other cortical areas
6.To complete the whole population of cells glial cells are born and send to the cortex
-Inhibitory neurones and oligodendrocytes are sent from the basal ganglia (ganglionic eminence)
-The astrocytes migrate from deeper in the cerebral cortex
7.Once the glial cells have arrived the subplate cells disappear – leaving a mature cortex with the right population of neuronal cells
Neurodebelopment timing
Nerve cells are born 6 months before birth
Glial cells are born anywhere between 3 months before to 3 months after birth
Clinical Significance
Rule:
Certain mutations disrupt the neuronal migration signals
Example 1
Lissencephaly - due to a loss of reelin -> improper migration signals -> an excessively thick cortex which leads to -> learning difficulties and seizures
Example 2
Heterotopia - due to a loss of doublecortin protein -> poor neuronal cell motility so unable to migrate -> accumulation of neuronal cells -> learning difficulties + epilepsy
Growth Cones
Once cells have set up location and matured, they need to develop their axons
The growing tips of neurons from which axons origin are called growth cones
These growth cones are made up of a lamellipodium which provide most of its area and are meshwork of actin that branch out into filopodia (actin bundles)
These filopodia act as stems for axon growth deciding direction of axon growth
Filopodia
Guidance signals:
Contains receptors that have been produced via morphogen transcription discussed earlier
Guidance signal-stimulation of this receptor causes actin filaments to grow allowing for longer filopodia to develop
Repulsive guidance signals will cause certain actin bundles to shrink too.
Example: a dorsal horn cell
Rule:An axon will follow guidance signals to certain waypoints. When they reach these way points they will be signalled to change direction to make sure they travel in their proper route
MOA:
Floor-plate guidance signals make the cell start growing axons towards the floor plate
Once the axon reaches the floor plate it will remove the receptors it had on its growth cone to find the floor plate and put different repulsive receptors in.
Axons will be repelled from the floor plate and up towards the brain
`ECM
Purpose: also helps guide direction of axon growth
MOA:
Filopodia also contain ECM binding proteins that only bind to specific channels of ECM
So, the axons are forced to go around areas where they aren’t needed
Synaptogenesis
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Def
Synaptogenesis - making connections w/ potentially useful partners
How it works
Lets assume axons have been fully developed and reached their respective locations: they then need to make connections with the right (useful) cells
Rule:
Axons explore their target region, by making ‘trial’ contacts w/ potentially useful cells
MOA:
1.The dendrites of the axon extend filopodia to seek contact from a passing axon
2.The filopodia and passing axon connect via the complimentary binding of both’s surface proteins
3.This triggers the production of a synapse between the two
)
*If binding proteins are not complimentary the filopodium retracts (e.g. muscle spindle afferent w/ an antagonist muscle motor neurone)
LTP
Synaptic plasticity and age
Rule:
-The mentioned mechanism of synaptogenesis isn’t a sustainable one. And so, the axon must get good identifying the ‘usefulness’ of passing axons. It does so by LTP
MOA:
1.After the process of synaptogenesis between a dendrite of the axon and another passing axon. After having produced the original trial synapse.
2.If the synapse between the dendrite and the passing axon activates, and the dendrite depolarises. This means this synapse has worked in concert worth all the other excitatory synapses in the neuron to produce an excitation
3.If this happens often, the synapse will strengthen as it has become more ‘useful’. In contrast, if the synapse doesn’t activate or does but produces no depolarisation then the synapse will weaken.
E.G. AMPA / NMDA receptors – single circuit
Background: A trial synapse has an:
(i) AMPA receptor (yellow) – fast ligand-gated ionotropic receptor (allow ions in through synapse) – this is a weak synapse
(ii) NMDA receptors (red) – only open and allow ions tin if they (i) are binding glutamate (ii) and their membrane is depolarised (basically if synapse is useful and is activated and can depolarise)
MOA:
- t/f: when glutamate is bound to this synapse AMPA receptors will allow ions in. But AMPA receptor
2.If this happens a lot, then the synapse is probably not doing anything useful -> it is weakened
E.G. AMPA / NMDA receptors – part of an effective circuit
MOA:
1.when glutamate is bound to this synapse AMPA receptors will allow ions in. Because synapse is part of an effective circuits. multiple AMPA receptors activate and so can produce enough AP to depolarise the membrane
2.and so due to glutamate and depolarisation, NMDA receptors are active. They open at active synapses allowing calcium ions in
3.These calcium ions allow the synapse to mature and introduce more AMPA receptors into its membrane and send retrograde messengers to the bouton increasing amount of NT
4.If this happens a lot, then the synapse is useful -> it is strengthened
*this is how neural circuits are refined and is what turns for e.g. random kicking movements of a baby when its born into its ability to run 100 miles when its 30
Rule:
-It is very effective and high in babies / foetus
-Plasticity fades with age as
wiring becomes more permanent
-Each synapse has a ‘critical period’ in which it can allow big changes to occur before it becomes more fixed
Examples of synaptic plasticity in babies
if a baby loses half their brain the other half can overtime control both sides of the body via LTP)
-Normally, inputs from both eyes have an equal share of the visual cortex. if one eye is compromised in early life (e.g. congenital cataracts), then synapses coming from that eye will not be part of an effective circuit and will make very few connections. The good eye will take over the bad eye’s visual cortex territory.