DEVELOPMENT OF NT

Question 1

What is being lost during development?

Answer 1

Synapses and cells are lost during development as observed by Victor Hamburger.

Question 2

What to motor neurons initially innervate?

Answer 2

Innervate multiple muscle fibres each receiving multiple inputs.

Question 3

What happens to innervation as a muscle matures?

Answer 3

Each fibre reveives input from only a single motor neuron.

Question 4

What happens for polyinnervation to become monoinnervation?

Answer 4

Synapses are eliminated and axons retract. This is through non random competition between synapses.

Question 5

Synaptic competition is activity dependent. What happens if you use tetrodotoxin on synapses?

Answer 5

Blocking activity with TTX actually leads to a reduction in synapse loss. This is becuase there is no competition and so there are fewer losers.

Question 6

What is the primary determinant of survival of synapses?

Answer 6

Coordinated electrical activity between pre and post synaptic cells.
Deliberate non-coordinated firing increases the rate of synapse loss.
This can be done by stimulating synapses artificially in a non coordinated manner.
(Cells that fire together, wire together).

Question 7

Another determinant of survival is the Punishment and Rewards systems of neurotrophins. How does this work?

Answer 7

The presence of BDNF triggers synaptic potentiation and maturation through TrkB signalling (Reward)
In contrast proBDNF suppresses synaptic transmission and causes axonal retraction via p75-NTR. (Punishment)

Question 8

What converts pro-BDNF to BDNF?

Answer 8

Matrix metalloproteinase.

Question 9

What does inhibition of matrix metalloproteinase cause?

Answer 9

Prevents strengthening of the synpase in response to pre and post synaptic synchronised activation. This suggests that synchronised activation in some way increases MMP processing of proBDNF to BDNF which then strengthens the synapse through TrkB signalling.

Question 10

What is the Hebbian Theory?

Answer 10

Donald Hebb -
Coordinated activity of a pre synaptic and post synaptic neuron strengthens the synaptic connections between them.
‘When axon A is near enough to excite axon B and repeatedly/persistently take part in firing, growth processes/metabolic changes take place in one or both cells such that A’s efficiency is increased.

Question 11

What is the function of these rewards and punishment systems of neurotrophins?

Answer 11

Operate in the refinement and focussing of CNS and PNS connections.

Question 12

What experiment can show an example of the reward and punishment system in the CNS?

Answer 12

Connection Focusing of Ocular Dominance Columns
Segregation of the LFN inputs in Layer 4 of the visual cortex is in eye specific columns (individual stripes). You can show this by injecting radioactive amino acids into one of of the adult animal. When this experiment is repeated in early development the visual cortex columns are not evidence but become evident after eye opening (3 weeks after ferret birth). This suggests activity plays a role. By preventing eye-opening in one eye during development (monocular deprivation results in most cells responding to light from only one eye. The dominance columns can be seen to have a different distribution. This suggests inputs compete for synaptic partners based on activity.

Question 13

The mechanisms operating in development appear similar to those found in learning and memory in the hippocampus. How?

Answer 13

High frequency stimulation of the presynaptic cell results in long lasting post synaptic response to induced action potentials. This is Long Term Potentiation.
Whilst low frequency stimulation of the pre synaptic cell results in long lasting decreased post synaptic response to induced action potentials. This is Long Term Depression.

Question 14

In what way is NMDAr a coincidence detector?

Answer 14

Hippocampal pre-synaptic neurons release glutamate when stimulated. The post synaptic cells have two kinds of glutamate receptors: AMPA and NMDA
If depolarising levels of sodium (ie enough to trigger an action potential) flow through AMPAr in response to glutamate release, this unblocks NMDAr channels, release calcium into the cell. (Calcium triggers a number of events contributing to synaptic potentiation.)
Thus, NMDAr is activated in response to presynaptic glutamate release AND post synaptic action potentials.

Question 15

What are some of the mechanisms operating for synapse potentiation?

Answer 15

Post-synaptic changes in AMPAr number and responsiveness (LTP increasing and LTD decreasing)
Increases in synaptic size
Pre synaptic changes in neurotransmitter release due to retrograde signals (NO, endocannabinoids, BDNF)

Question 16

What also happens in development in terms of potentiation?

Answer 16

Block of NMDAr in the visual cortex prevents the effects of monocular deprivation
Blockade of TRkB signalling impairs ocular dominance column formation
BDNF loss affects LTP
ProBDNF induced LTD
BDNF is secreted in response to high frequency stimulation
BDNF potentiates glutamate release from pre synaptic cells

Question 17

Neuronal identity is set up in early patterning determining the set of transcription factors turned on to dictate the type of neurons that progenitors give rise to thereby determining the characteristics and behaviours of the mature neuron. Many of the transciption factors remain on in the differentiated neurons. Give an example the neurotransmitters expressed in dILA inhibitory neurons?

Answer 17

NPY
Nocicpetin
Galanin
Enkephalin
Dynorphin

Question 18

What are some of the neurotransmitters expressed in the dILB excitatory neurons?

Answer 18

CCK
PACCP
TAC1
GRP
Neurotensis
Somatostatin
Calcitonin
NPFF

Question 19

Interactions with targets can also change the features of the mature neuron. Give an example of this.

Answer 19

Motor neurons innervating the triceps and pectoral muscles develop monosynaptic connections directly with proprioceptive neurons whereas motor neurons innervating the cutaneous maximus and lattisimus dorsi receive polysnaptic input from interneurons. This is controlled by Glial derived neurotrophic factor secreted from the cutaneous maximum and latissimus dorsi which turns on transcription of Pea3 in the motor neurons.

Question 20

Give an example of how circuit completion relies on target feedback?

Answer 20

Muscle expressed NT3 induces expression of the transcription factor ER81 by 1a proprioceptors. This is essential for the development of the central projection. KO out Er81 lead to failure of the 1a central projection to reach the ventral horn and form monosynaptic connections with the appropriate motor neurons.
This is a kind of quality control -feedback from the target determines the final patterns of both dendritic and axonal connections.

Question 21

Target may or may not be depended on inputs. Give examples of each.

Answer 21

Muscle spindles need sensory input to differentiate.

Merkel cells (specialised epithelium) develop before sensory innervation.

Question 22

What is functional property maturation?

Answer 22

Some properties change as targets mature.

Eg sweat gland motor input changes from being noradrenergic to cholinergic and the glands mature and change function.

Question 23

What are other examples that synaptic function continues to evolve throughout development and during mature function.

Answer 23

1. Subunit expression can change (ACh)
2. Changes in ion channel subunits (early APs are calcium driven and change to sodium driven)
3. NT responses can change from excitatory to inhibitory (GABAa switch between inwards and outwards Cl- currents)