Lecture 11- Neuronal migration in brain development II (interneurons+hippocampus) Flashcards
Where are cortical interneurons generated?
- in the ventral forebrain (telencephalon), in the ganglionic eminence (GE)
- more specifically in the MGE (medial ganglionic eminence)
- in humans and non-human primates there may be another site of origin: the cortical surface
How far do cortical interneurons have to migrate in comparison to pyramidal neurons?
-much longer migration than in pyramidal neurons
How do interneurons migrate?
-migrate from the ganglionic eminence tangentially into the neocortex (parallel to ventricular surface) and then radially to get down or up within the cortex
How can you study interneuron migration?
- interneurons produce the neurotransmitter GABA
- glutamic acid decarboxylase 67(GAD67) is an enzyme required for the synthesis of GABA
- using gene technology to create a GAD67 promoter-knockin-green fluorescent protein (GFP)
- GFP will be expressed by all interneurons that express GAD67 (which is pretty much all of them)
How do interneurons know where to migrate and in what fashion do they migrate?
- don’t have glia so use guidance cues in the environment
- migrate in streams, at first have just one stream later on have two
What are the three parts into which the ganglionic eminence of the ventral telencephalon can be subdivided?
- MGE= medial ganglionic eminence
- LGE= lateral ganglionic eminence
- CGE= caudal ganglionic eminence
What are the three streams of interneuronal migration?
- The one going via the marginal zone
- The one going via intermediate zone/subplate
- The one going via subventricular zone
- all go tangentially until they get to the cortex and then radially to the cortical plate, this can be pial directed or ventricle directed
Which stream of interneuron migration is first, second and third?
- Interneurons migrate into the cortex in distinct tangential routes through the MZ, followed vy IZ/SVZ and at later stages SP (subplate)
- multidirectional migration within the tangential streams
What do the interneurons require guidance cues for?
- interneurons migrate through an environment with no supporting cells (glial fibres or guidepost cells)
- guidance cues can direct their migration
- guidance cues are required for avoidance of the presumtive striatum and preoptic area
- so have cue that say come here and cues that say no go zone here (these are particularly in the striatum and the preoptic area)
What is the migration of interneurons called?
- gudiance-guidance migration
- require guidance cues, tangential migration within the cortex and radial migration into the cortical plate
What is the MGE (medial ganglionic eminence) a source of?
- source of cells that migrate tangentially to the:
a) neocortex (cortical interneurons)
b) hippocampus
What is LGE a source of?
-gives rise primarily to cells that migrate radially to the striatum and rostrally to the olfactory bulb
What is CGE a source of?
-source of cortical interneurons (20% estimated)
What are the guidance cues directing the interneuronal migration into the cortex?
-attraction cues= BNDF and NT4
HGF
GDNF
Neuregulin
GABA
SDF
Dopamine
-repulsion cues= Semaphorin/Neuropilin
Slit
How do the interneurons move through the tissue, how do they “know” where to go?
- the process of migration occurs by the dynamic extension/retraction of neuritic processes and somal translocation
- extension of growth cone and leading process
- translocation of the soma
- retraction of the trailing process
- directional migration achieved through branch extension
- *-each soma has branches, each end has growth-cone-like tips= sensing devices
- if you like something in one area the branch will extend in that area, if not it will retract**
-the soma will only move after the branches have explored the surroundings, not dragged by the growth cone
How quickly do interneurons and pyramidal neurons migrate?
(this is the true info! do not pay attention to the previous lecture)
interneurons= 40 microns/hour
pyramidal neurons= 60 microns/hour
What does the embryonic cortex look like during neuronal migration? (picture only)
-green= interneurons
What are some of the ways of studing interneuronal migration?
- graft of GFP(+)MGE in a forebrain slice (upper left in picture)
- coculture of cortical explant and GFP(+)MGE on laminin (upper right in picture)
- GFP(+)MGE cultured on dissociated cortical cells (bottom left in picture)
- many possibilities, can do timelapse imaging, can look at a slice, can provide artificial substrate and see how the interneurons react, can add or remove factors to see the effect…
(for interest only)
What are the parts of a migrating interneuron called and what are their functions?
- soma: contains the nucleus and cytoplasm
- MTOC: microtubule organizing centre
- Neurite process (branches)
- Growth cone-like tips: navigational device
What is the interneuronal migration also called (based on the soma movement)?
- saltatory migration
- the soma is not just dragges by the tips, it “jumps” when the branch establishes that that is the place to go
- the soma sends out “feelers” and will not move until a predominant direction is found
- after the jump more branches emerge and start feeling out the surrounding to prepare for the next “jump”
What is the role of Jnk1 in interneuronal migration?
-cortical interneurons require Jnk1 to enter and navigate the developing cerebral cortex
Where do GE-derived interneurons reside?
- mainly cortex and hippocampus
- these two structures are not too far away from one another in the embryonic brain
What is layering like in interneurons, where do the early and late born interneurons end up?
- early born in lower layers (old)
- late born in upper layers (young)
- so the pyramidal neurons and interneurons despite coming from different places= end up in same layer arrangement
- this was revealed dong birthdate analysis and transplantation studies
What is the classification of interneurons like? (just for interest)
- interneurons are a highly heterogenous population
- this diversity is required for the specialised role these neurons play for cortical function
- subtype classifications are based on three major criteria which include:
a) Molecular profile- expression of calcium binding neuropeptides such as Parvalbumin (PV) etc.
b) Morphology: soma size and shape, dendritic and axonal arborization, location of postsynaptic connections
c) Electrophysiology: the firing properties that characterise interneuron activity within the cortical cicrcuitry (fast spiking, regular spiking etc…)
What is the origin of hippocampal interneurons?
(different from the cortical interneurons!)
- originate in the CGE (caudal ganglionic eminence) and MGE as well
- the MGE gives rise to some cortical and some hippocampal interneurons
What does the LGE give rise to?
-interneurons of the striatuma and olfactory bulb
What does this picture show?
- migration of interneurons and pyramidal neurons
- all of this is happening at the same time
Are there any unique human and non-human primates interneuons? If so what are they?
- unique interneurons, displaying different morphologies to the rodent ones are found in primates and humans, e.g. the double bouquet interneuron
- this indicates that not only are more interneurons required but newer forms have also been generated in higher organisms (with larger brains)
Are there neuron progenitors in the cortex (humans)?
- ongoing debate, some studies claim yes, some claim no
- apparently some have identified proliferating cells which express Mash1 and NkX2.1 which are transcription factprs for the MGE in rodents
- so could be a source but maybe not…
What does new research suggest about interneuron origins?
-thought that MGE is the primary source of cortical interneuron, some studies now suggest that CGE is more important than MGE
How do you remember developing telencephalon?
-looks like batman!
Where is the hippocampus in the developing telencephalon?
- DG= dentate gyrus
- CA3 and CA1= neurons
Are hippocampal neurons guided by glial guides?
-yes
- similarities between hippocampus and the cortex
- green= ventricular is at the top
- have fibres coming down= something using them as scaffold
What happens to the hippocampi in Reelin-null mutants?
- migratory defects
- cells not aligned, fibres also affected
- A= normal, B= reelin null
Can you rescue the reelin-null hippocampus?
-can rescue some of the aberrant fibres when exposed to normal reelin during development
What happens in the adult hippocampus?
- proliferating cells in the SGZ(subgranular zone) of the dentate gyrus (DG) give rise to young neurons that migrate a short distance and differentiate into hippocampal neurons in the granular cell layer
- the subgranular zone of the adult hippocampus is where adult neurogenesis occurs
What transcription factors are expressed on hippocampal progenitors and maturing neurons?
- Sox2 positive hippocampal progenitors go through a transitory phase of Tbr2 positive progenitors that migrate and differentiate into neuroD positive neurons
- same TFs as in the cortex!
How does reelin affect dendrite formation?
- Reelin stabilizes dendrite formation
- the cytoskeleton is stabilized and the granule cell dendrites are anchored to the marginal zone
- when reelin signalling is blocked or deficient, there is increased motility of the DG granule cells and dendrites are neither stabilized nor anchored to the marginal zone
- in the picture: granule cell shown with the dedrites extending toward the marginal zone (MZ) containing Reelin (red= reelin)
What are the functions of Reelin in the hippocampus? (3)
- essential for the proper formation of the radial glial scaffold in the hippocampus (as it is in the cortex)
- required for lamination of CA1, CA3 neurons (as in the cortex)
- stabilizes the cytoskeleton in the leading process (dendrite) (like in the cortex)
