06_Brain Wiring_Q and A_Jonathan

Question 1

How do we make the right map in development?

Answer 1

1. Migration
2. Guidepost cells
3. Growth cones
4. Pioneer neurons
5. Labeled pathways
6. Chemoattractants and chemorepellants
   a. Soluble
   b. Membrane-bound
   i. Local
   ii. Long-range
   iii. Gradients

Question 2

he complexity in human behaviors comes about because of the vast number of neurons and glial and therefore the exponentially greater number of permutations in information processing that occurs in our brains; not because our nervous systems forms or functions by fundamentally different mechanisms.

Answer 2

he complexity in human behaviors comes about because of the vast number of neurons and glial and therefore the exponentially greater number of permutations in information processing that occurs in our brains; not because our nervous systems forms or functions by fundamentally different mechanisms.

Question 3

cortical layers contain both excitatory principal cells (glutamatergic) and interneurons (GABAergic; usually inhibitory).

Answer 3

cortical layers contain both excitatory principal cells (glutamatergic) and interneurons (GABAergic; usually inhibitory).

Question 4

Where do principle neurons arise? Where do interneurons arise?

Answer 4

• principle neurons ==> the ventricular zone of the pallidum (cortex)
• interneurons ==> the basal telencephalon (subpallidum), which includes the lateral and the medial ganglionic eminence (LGE and MGE, respectively).

Question 5

How do GABAergic interneurons migrate?

Answer 5

• In contrast to radial migration, GABAergic interneurons use distinct tangential migratory routes.
• Migration of these interneurons is guided by chemical cues and their cognate receptors.

Question 6

Schizophrenia details:

Answer 6

Disruption of this signaling (and thus proper migration during development has been suggested to contribute to the etiology of a number of disorders, including schizophrenia. Schizophrenia is a neurodevelopmental disorder that usually manifests in adolescence. Both positive (hallucinations) and negative (social withdrawal, lack of affect) symptoms, as well as deficits in working memory, characterize this disease. While symptoms appear later in life, the roots of the disorder lie in improper development of the brain. Specifically, deficits in neuronal migration, maturation, myelination, synaptic pruning and synaptic function have all been described in the brains of schizophrenic patients and in animal models of this disease. Multiple susceptibility genes interact with various different environmental stressors in the expression of schizophrenia.

Question 7

What are two genes implicated in schizophrenia?

Answer 7

• deficits in signaling between neuregulin 1 and its receptor ErbB4

Question 8

What are gamma oscillations?

Answer 8

• Brain cells oscillate together at usu at 40 Hz (25 to 100)
• Synchronization of activity in the cortex results in these gamma oscillations, and they are important for cognition, learning and memory.

Question 9

What controls gamma oscillation frequency?

Answer 9

• specific subsets of GABAergic interneurons that regulate the firing of glutamatergic principal neurons in the cortex.

Question 10

Which GABAergic interneurons specifically control gamma oscillations?

Answer 10

• fast-spiking GABAergic interneurons that express the calcium binding protein, parvalbumin

Question 11

What is the connection between neuregulin 1 and receptor ErbB4 and schizo and gamma oscillations?

Answer 11

• Signaling mediated by neuregulin1 and its receptor ErbB4 is critical for the migration, differentiation and survival of these fast-spiking/parvalbumin interneurons.
• Loss of these interneurons or disruption of their function results in a loss of power in gamma oscillations that mimics the pattern seen in schizophrenics.

Question 12

What is the role of GABAergic interneurons in the development of Thalamocortical Afferents (TCA)?

Answer 12

• Immature GABAergic interneurons and neuregulin-1/ErbB4 also play a critical role in the establishment of axon pathways between the developing thalamus and the cortex: the thalamocortical afferents (TCA).
• immature GABAergic interneurons, called corridor cells, act as guidepost cells, “steering” the growth cones of nascent TCAs as they traverse the developing brain.

Question 13

Where do “corridor cells originate”?
Where do they migrate?
What do they do there?
Describe the mechanism of corridor cells guiding TCAs.

Answer 13

• derived from the LGE
• migrate tangentially into the MGE
• form a permissive zone between the MGE and the primordial globus pallidus—areas that are repellant (because of specific factors expressed) to TCAs.
• The corridor cells express membrane-bound neuregulin-1 and growth cones of the TCAs express ErbB4.
• This dual pattern of expression lays down a “safe zone of passage” for the TCAs through the otherwise hostile territory of the LGE/globus pallidus.

Question 14

Explain the function of Guidepost cells.

Answer 14

• function like kiosks, providing directions can alter the trajectory of outgrowing axons by altering intracellular signaling within the growth cones.
• In vertebrates, in addition to the corridor neurons, both the Cajal-Retzius cells in the hippocampus and the subplate neurons in the cortex perform a similar role.

Question 15

Pathfinding:

Answer 15

Specific chemical cues and subsequent cellular signaling is critical not only for migration, but also for axon pathfinding. These cues are both short-range and long-range chemical signals that can either attract or repel outgrowing axons.

Question 16

What are Growth Cones?

Answer 16

Developing neurons use beautiful and highly specialized structures called growth cones to sniff out specific messages in their environment that guide them along their route to their appropriate targets. Growth cones are highly dynamic, and specialized endings, sheet-like structures called lamellipodia, and finger-like protrusions called filopodia, both at the tips of growth cones, navigate the developing brain terrain and direct axons to their proper destinations. As these growth cones reach critical choice points where the environment and the cues change, their shape and the speed at which they move also change (see figure above). Once they reach their final destination, they then differentiate into the specialized sub-cellular structures that become the presynaptic terminal.

Question 17

Explain Axon guidance. What are the two forms of signals (ie structural and diffusible)?

Answer 17

As axons traverse the developing nervous system, they are constantly guided, in a positive fashion by some molecules (attractants) and in a negative fashion by others (repellants). Axon guidance molecules can be secreted or tethered to membranes or basal lamina (extracellular matrix). In the former case, these factors tend to function as long-range signals and to be expressed in gradients in target tissues; these gradients being in an inverse concentration to the expression of receptors in outgrowing axons that bind them (see below). In contrast, membrane-associated signals usually serve as short-range signals policemen directing axon traffic to make the right turns in the local neighborhood

Question 18

What are Pioneer neurons?

Answer 18

• These are specialized cells in the developing nervous system that are the first to brave uncharted territory.

Question 19

Compare the filopodia activity of pioneer cells vs follower cells.

Answer 19

• Their growth cones have many active filopodia
• In contrast, follower neuron growth cones, which latch onto the pioneer’s trail and form fascicles, have growth cones that are much simpler, with few filopodia.

Question 20

Explain the altruistic nature of some pioneer cells.

Answer 20

Some of these pioneer neurons are transitory. For example, Rohon-Beard neurons are primary sensory cells in the developing spinal cord. They not only pave the way for the follower neurons, but also transmit sensory information from the periphery in the early stages of development. They undergo programmed cell death at the time that the dorsal root ganglia (DRGs) develop to take over this role.

Question 21

Explain the difference between Trophic vs. tropic molecules

Answer 21

• trophic molecules support growth and survival

* tropic molecules guide.

Question 22

What are some factors both tropic and trophic?

Answer 22

• neurotrophins and their receptor Trks (which are receptor tyrosine kinase receptors
• There are too many to list, but these are highlighted
o ECM
o CAMs (cell adhesion molecules)
• N-CAM
• Cadherins (Ca-dependent adherins)
• Chemoattractants and chemorepellants (e.g., Slit, ephrins, netrin, semaphorin and neurotrophins

Question 23

Explain the roles of soluble Chemoattractants and chemorepellants (e.g., Slit, ephrins, netrin, semaphorin and neurotrophins)

Answer 23

• promote longitudinal growth and guide axons’ direction and decussation (crossing from one side to the other, eg optic chiasm)
• both diffusible signals and others require actual contact.
• can have different instructional roles depending on where and when they are expressed.
• Sometimes a single ligand/receptor pair can attract; sometimes repel, and the change depends upon the concentration of signaling molecules within the growth cone where the molecules act

Question 24

Explain how Netrin and Slit regulate the crossing (decussation) of axons in the spinal cord.

Answer 24

• These factors are expressed at the midline floor plate.
• netrin also initially acts as a chemoattractant guiding axons towards the midline.
• before axons cross, they do not respond to slit or another class of molecules called the semaphorins.
• However, once the axons cross the midline, they lose their sensitivity to netrin and become repelled by slit and the semaphorins that are expressed at high levels in the midline floorplate.

Question 25

Retinal ganglion cell axons express receptors called Ephs and collicular cells express ligands called ephrins in inverse gradients.

Answer 25

Comparison of gradient cues allows mapping to appropriate postsynaptic sites. Because of the continuous nature of these opposing gradients of ephrins and their cognate Eph receptors, there can be a unique combinatorial match that allows the axon on the appropriate place on the retina to recognize and form a functional contact with the appropriate place on the tectum or colliculus.

Question 26

Netrins:

Answer 26

o Multifunctional; can repel or attract (and turn growth cones)
o Netrin receptors; DCC (deleted in colorectal cancer carcinoma family) expressed in retinal ganglion cell (RGC) axons
o Have high affinity for cell membranes: short range guidance cues
o Expressed by midline floorplate neurons in vertebrates at optic chiasm
o Turning response is dependent on [cAMP] in growth cone: low [cAMP]/PKA yields repulsion; high [camp]/PKA: attraction
o Turning response is modulated by b1 integrins (a component of the laminin receptor) via changes in PKA

Question 27

Slit:

Answer 27

o Large secreted protein
o Like netrin, Slit is expressed by midline floorplate neurons and at chiasm and is multifunctional (repel, attract, turn)
o Receptor: Roundabout (Robo) family
o Plays a major role in preventing ipsilateral axons from crossing at the optic chiasm and preventing those that do cross (commissural axons) from recrossing

Question 28

Semaphorins:

Answer 28

o Multifunctional (although predominantly repellant)
o First ones identified through a screen for molecules expressed on axon fascicles in grasshoppers and by purifying a vertebrate inducer of growth cone collapse
o The receptors consist of a complex of neuropilins and plexins
o Neuropilin 1 is localized to growth cones
o Semaphorins are bound to cell surfaces or the ECM (i.e., can be secreted or membrane-bound)
o Semaphorins cause dramatic and immediate growth cone collapse

Question 29

Ephrins:

Answer 29

o Regulate formation of topographical maps by orthogonal systems of molecular gradients in the retina and in the tectum: such gradients were first postulated by Sperry
o Classes of Ephrins and their receptors (Ephs: receptor tyrosine kinases):
• Ephrin A: GPI-linked membrane associated ligands that interact with EphA receptors
• Ephrin B: ligands have a transmembrane domain and bind EphB receptors
o Ephrin signaling governs cytoskeletal dynamics and growth cone turning by regulating small GTPases: activates RhoA and inhibits Rac-1
o Anterior-Posterior topography in retinotectal (collicular) system mediated by repulsive gradients of Ephrin A (in tectum) and a complementary gradient of EphA receptors in RGC axons: Axons with highest levels of EphA map to tectal cells with lowest levels of Ephrin A
o Dorsal-Ventral topography: attractive signals between gradients of both Ephrin B and EphB in retina and tectum

Question 30

What are Neurotrophins?

Answer 30

• molecules such as nerve growth factor (NGF), brain-derived growth factor (BDNF), and neurotrophin 3 (NT-3).
• These molecules play critical roles in promoting the growth and survival of neurons during development, in modulating synaptic function, and in regeneration and repair in adults.
• can also have tropic (i.e., axon guidance) properties, which have been shown to be particularly important in establishing the proper pattern of innervation in the peripheral nervous system.