Lecture 5: Construction of Neural Circuits Flashcards
What is the role of growth cones in axon navigation?
Growth cones are highly motile structures that interpret extracellular signals to navigate axons toward their targets.
What types of signals do growth cones respond to?
Growth cones respond to attractive and repulsive guidance cues, including:
* Cell adhesion molecules (CAMs)
* Ephrins
* Netrins
* Semaphorins
* Slits
* Neurotrophic factors
* Morphogens
What is the process that occurs after axons reach their destination?
After reaching their destination, axons stop elongating, branch extensively to form a terminal arbor, and establish specific synaptic connections.
What are the main types of cell adhesion molecules expressed in the nervous system?
The main types are:
* Extracellular matrix molecules
* Ca2+-independent cell adhesion molecules (CAMs)
* Ca2+-dependent adhesion molecules (cadherins)
* Ephrins
What is the function of cell adhesion molecules (CAMs)?
CAMs mediate contacts between cells or cells and substrates via homophilic or heterophilic interactions.
Define self-avoidance in the context of neuronal processes.
Self-avoidance is the regulation of dendritic and axonal arbor sizes to avoid overlapping among processes of the same neuron.
What is tiling in neuronal processes?
Tiling is the regulation of territory among processes of different neurons with the same function to avoid overlapping.
What are the Drosophila proteins associated with self-avoidance and tiling?
The associated proteins are DSCAM1 and DSCAM2.
What determines the homophilic binding specificity of Drosophila Dscam1?
The homophilic binding specificity is determined by its Ig2, Ig3, and Ig7 domains.
What is the role of vertebrate Dscams in synaptic specificity?
Vertebrate Dscams may mediate de-adhesion in tiling and self-avoidance by down-regulating the function of cell-type-specific adhesion molecules.
What are the clustered protocadherin (Pcdh) genes?
The Pcdh genes include α, β, and γ, which can yield distinct isoforms by alternative splicing.
What is the effect of γ-mutation in protocadherins?
γ-mutation disrupts self-avoidance.
What is the effect of α-mutation in protocadherins?
α-mutation causes defects in tiling, leading to overlapping projections.
List the mechanisms that promote the establishment of synaptic specificity.
The mechanisms include:
* L1-CAM
* Cadherins
* Protocadherins
* Neurexin/Neuroligin
* Netrin
* Wnt
* Semaphorin
What does the chemoaffinity hypothesis propose?
The hypothesis proposes that neurons possess unique molecular tags (CAMs) that enable them to recognize appropriate synaptic partners.
What are the predictions of the chemoaffinity hypothesis?
The predictions include:
* Molecules are expressed at the time of synapse formation
* Molecules are expressed in complementary patterns in presynaptic and postsynaptic neurons
* Non-synaptic partners express less compatible molecules
* Manipulation of the molecule results in circuit miswiring
What is the first step in synapse formation?
The first step is the recognition of the target by the immature presynaptic terminal, mediated by adhesive factors.
What drives the elaboration of pre- and post-synaptic specializations?
It is driven by:
* Release of signaling molecules (e.g., growth factors, neurotransmitters)
* Recruitment of synaptic specific adhesion molecules and neurotransmitter receptors
True or False: Different isoforms of Eph and EphRs contribute to synapse specificity.
True
Fill in the blank: The affinity of cis-dimers for trans-interaction partners depends on their _______.
composition
Formation of corpus callosum: Axon guidance before midline crossing
EphA Rs are expressed in VZ and CP and repel Ephrin A4 (EfnA4)-positive callosal axons
Formation of corpus callosum: Axon guidance during midline crossing
Callosal axons express Slit Rs (Robo1 + Robo2) → cortical axons avoid Slit- expressing ventral and dorsal midline territories
Sema3C (midline gradient) + Neuropilin-1 (Nrp1) R on callosal axon growth cones = attractive cue
Formation of corpus callosum: Axon guidance after midline crossing
Expression of ephrinB1 suppresses
Sema3C/Nrp1 effect
Formation of Spinal Cord
Commissural Tracts: Axon guidance BEFORE midline crossing
- Pre-crossing axons express Robo3 which interacts with Dcc, promoting extension to the floor plate in response to Netrin-1.
- Robo3 might also prevent Slit repulsion by interacting with the Robo1/2 Rs.
- cleavage of PlexinA1 suppresses repulsion by Sem3B
Formation of Spinal Cord Commissural Tracts: Axon guidance AFTER midline crossing
- Robo3 is down-regulated, and Robo1/2 interaction with Slits blocks the Dcc- Netrin-1 attractive signalling.
- Lack of Calpain allows PlexinA1 to reach the membrane where it interacts with Neuropilin2, triggering midline repulsion by Sema3B
Topographic map
neighboring points in the periphery connect to adjacent locations in the CNS - e.g. retinotopic map (retina-
tectum/superior colliculus)
Retinotopic map
Based on chemoaffinity theory:
EphB + Ephrin B
EphA + Ephrin A
Axons w/low EphA can only target region with high ephrinA and vice versa
L: high EphA molecule, M:high ephrin A ligand so D: high EphB molecule, V:high ephrin B
L: high EphB molecule, M: high ephrin B ligand so D: high EphA molecule, V: high ephrin A
trophic support (and experiment)
Target-derived trophic support required for survival of neurons
- Importance for maintenance and validation of connection
Remove target limb bud -> ventral
horn motor neurons die.
* Add extra limb -> ventral horn recruits additional motor neurons.
→Neurons compete for limited
trophic support
pre-natal and post-natal (Trophic interactions regulate number and pattern of neuronal connections)
pre-natal: Poly-neuronal innervation (1:1)
Competition For space and trophic
support (and influenced by electrical activity)
post-natal: Synapse elimination and enlargement of synaptic territory (1:many)
Trophic support via trophic factors (neurotrophins)
released by targets and required for survival of innervating neurons
- Neuronal inputs compete for these ‘limited’ factors
- Ensure formation and maintenance of appropriate numbers of connections
- Promote elaboration of arbors to support these connections
Neurotrophins and Receptors examples
- Nerve growth factor (NGF)
- Brain-derived neurotropic factor
(BDNF) - Neurotrophin-3 (NT-3)
- Neurotrophin 4/5 (NT-4/5)
- Neurotrophin Rs are ALL tyrosine
kinases (except for P75NTR) - p75NTR may signal independently or function as co-R of Trk Rs
The molecular basis of trophic interactions
Different neurotrophins have different effects on different target neurons depending on the Rs and the intracellular signaling cascade activated
Proposed models for the action of Drosophila Dscams
Drosophila Dscam1 mediates homotypic repulsion in tiling and self-avoidance. The homophilic binding specificity of Dscam1 is determined by its Ig2 (red), Ig3 (green) and Ig7
(purple) domains. The binding between two Dscam isoforms only
occurs if all three Ig domains (i.e. Ig2, Ig3 and Ig7) are identical (homophilic)
Proposed models for the action of vertebrate Dscams
may mediate de- adhesion in tiling and self-avoidance by down- regulating the function of some unknown cell- type-specific adhesion molecules
