Synaptogenesis

Question 1

Pre- and Post-synaptic specializations form at sites of active contact

Synapse formation in the CNS

Answer 1

• Dendritic filopodium contacts axon
• Synaptic vesicles and active zone proteins recruited to presynaptic membrane
• Receptors accumulate at postsynaptic membrane

Question 2

What we know about synapse formation comes from the NMJ

Neuromuscular junction formation

Axon terminal, muscle, and basal lamina in between

Answer 2

1. Motor neuron axon secretes a protein called
   agrin into the basal lamina
2. Agrin receptor on muscle receives Agrin signal
   * MuSK – muscle specific kinase
3. MuSK activates Rapsyn
4. MuSK and Rapsyn together cluster Acetylcholine receptors into plaques
   * Reciprocal signaling is necessary for synapse
   formation
   * Not just axon to muscle!
   * Basal lamina can trigger calcium influx into axon terminal
   * This causes release of more neurotransmitter
   * Positive feedback

Size of receptor cluster dictated by neuregulin secreted by axon

Question 3

Cell Adhesion Molecules

Not just for axon guidance

Answer 3

• Cell adhesion molecules can regulate synapse
  formation and stabilization
• Best characterized synaptic cell adhesion
  molecules: Neurexin and Neuroligin

Question 4

Neurexin

Answer 4

3 Neurexin genes and multiple isoforms in the brain

Typically pre-synaptic

Question 5

Neuroligin

Answer 5

4 Neuroligin genes and multiple isoforms in the brain

Typically post-synaptic

Question 6

Deletion of all Neurexins causes:

Answer 6

• Decreased pre-synaptic calcium influx
• Decreased synaptic release probability
• Decreased synapse number (only in some brain regions)
• Differences maybe due to only partial redundancy between Neurexins

Question 7

Neuroligins are targeted to distinct post synaptic types

Answer 7

• Neuroligin 1 – excitatory synapses
• Neuroligin 2 – inhibitory, dopaminergic, and cholinergic synapses
• Neuroligin 3 – excitatory and inhibitory synapses
• Neuroligin 4 - glycinergic synapses

Question 8

Neuroligin functions at the synapse

Answer 8

• Increasing Neuroligin protein levels can increase synapse density and synaptic transmission
• Loss of Neuroligin function causes decreased synaptic transmission but no change in synapse number

Have diverse functions at the synapse important for synaptic activity

Question 9

Neuropsychiatric disorders are linked to Neurexin mutations

Answer 9

• Large genomic deletions that remove Neurexin 1 are linked to: schizophrenia, tourette syndrome, intellectual disability, epilepsy, autism
• Mutations in Neuroligin 3 and Neuroligin 4 are linked to autism spectrum disorder
• Expression of an autism-linked Neuroligin 3 mutant gene in mice causes synaptic and behavioral abnormalities
• Deficits in social behavior
• Proxy for autism-like behavior

Question 10

Synapses change with development and activity

• Axons leave the retina and go to the LGN (thalamus)
• Axons leave the LGN and go to striate cortex (visual cortex)

Answer 10

• Axon pathfinding can proceed using all of the mechanisms we have previously discussed but synaptic refinement requires synaptic pruning

Question 11

Types of synaptic refinement

Answer 11

1. Changes in synaptic capacity
2. Synaptic rearrangement
3. Synaptic segregation
4. Programmed cell death

Question 12

Changes in Synaptic Capacity

Answer 12

The neuromuscular junction
1. Start with an alpha motor neuron that innervates
multiple muscle fibers
2. Maturation – refines so each motor neuron innervates 1muscle fiber

Question 13

Synaptic Loss Requires Muscle Activity

Answer 13

• Silencing muscle = retain polyneuronal innervation
• Activating muscle = accelerates removal of all but 1 innervating neuron

Question 14

Temporal Aspects of Motor Neuron Capacity Refinement

Answer 14

1. Loss of post-synaptic acetylcholine receptors on the muscle fiber
2. Disassembly of the pre-synapse
3. Axon retraction
   * This is due to a loss of activity at a subset of acetylcholine receptors
   * Loss of activity at all receptors causes maintained polyneuronal innervation

Question 15

Activity Dependent Synaptic
Rearrangement

Answer 15

Change in how many synapses individual input
neurons have on receiving neuron
* Receiving neuron maintains same total number of
synapses but varies how many come from each input
* Is due to neural activity and synaptic transmission
* Final steps of address selection

Change in which neurons axon synapse on
* Due to neural activity as well
* Classic example is the visual system
* Segregation of eye-specific inputs in the cat LGN

Question 16

Waves of activity occur across the retina during development

Answer 16

• Retinas do this independently
• This means that neurons from one retina fire simultaneously which strengthens their synapses on target neurons in the LGN
  Also called Hebbian synapses – First posited as a possible mechanism of synapse remodeling by Donald Hebb in the 1940s.

Question 17

Synaptic Plasticity

Strengthening or weakening synaptic connections

Answer 17

Two rules for synaptic modification
* Fire together, wire together (Hebbian modifications)
* Fire out of sync, lose their link

A single synapse has little influence on firing rate of postsynaptic neuron.
* Activity of a synapse must be correlated with activity of many other inputs converging on the same postsynaptic neuron.

Question 18

Excitatory synaptic transmission in the immature visual system

Answer 18

Receptors can be metabotropic or ionotropic

Question 19

Ionotropic glutamate receptors can be further classified as:

Question 20

Ionotropic glutamate receptors can be further classified as:

AMPA receptors

Answer 20

glutamate-gated ion channels

Question 21

NMDA receptors

Answer 21

Ion channels with unique properties
* Voltage gated due to Mg2+ at the channel
* At resting potential, Mg2+ block channel
* Further depolarization leads to Mg2+ is displaced allowing current to pass
* Also unique because it conducts Ca2+
* Magnitude of Ca2+ passing through the channel signals pre- and post-synaptic activity

Question 22

Long-term synaptic potentiation

Answer 22

• It was hypothesized that NMDA receptors serve as Hebbian detectors of simultaneous pre- and postsynaptic activity
• Ca2+ could serve to trigger downstream modulators of synaptic effectiveness
• Experiments indicate this is true – strong NMDA
  receptor activation strengthen synapses through long-term potentiation (LTP)

Question 23

What changes downstream of Ca2+ cause strengthing?

LTP results from AMPA receptors addition

Answer 23

• Experiments show that continued depolarization/ glutamate release causes increased AMPA receptors clustering at post-synapse
• This leads to longer depolarization with stimulation
• LTP

Question 24

LTD: Long-term synaptic depression

Answer 24

• Neurons that fire out of sync lose their link
• Rather than Ca2+ with consistent depolarization, consistent low levels of Ca2+ due to decreased synaptic activity decrease synapse effectiveness
• Converse of LTP, consistently low Ca2+ levels lead to a reduction of AMPA receptors at the synapse
• Leads to decreased likelihood and amplitude of firing

Question 25

LDP: the underlying reason for reduced visual responses with monocular deprivation?

Answer 25

Control – normal visual cortex showing ocular dominance columns * Stripes correspond to input from two eyes * Permanently close one eye, columns from that eye are reduced and those from opposite eye expanded * Can be reversed if eye is opened * Ability to modify columns is not infinite * Loss of input from one retina- Critical period exists during which inputs can modify synaptic contacts/ocular dominance columns * After 6 weeks of age in macaques the innervation pattern is cemented

Question 26

Critical period in development

Answer 26

* Spemann found that Spemann-Mangold organizer transplantation could induce a second axis in the host * But only during a certain period of development before the host cells had already been committed to a different fate

Question 27

Critical period in behavior

Answer 27

* Konrad Lorenz found that social attachment formed within a certain period of time for graylag geese * Within 2 days of hatching, goslings would imprint on a moving object and treat that object as their mother

Question 28

Critical period at the synapse | Not permanently modifiable after timepoint of development or activity?

Answer 28

* Early in development, large scale changes of innervation patterns can change * This is not possible at later/adult stages * In the adult, plasticity is restricted to local changes in synaptic efficacy

Question 29

Hypotheses on critical period endings

Answer 29

1. Plasticity diminishes when axon growth stops 2. Plasticity decreases when synaptic transmission matures 3. Plasticity decreases when cortical activation is constrained | Astrocytes can also regulate closing of the critical period ## Footnote Understanding the critical period could provide some insight into why recovery is limited after injury to the adult brain

Question 30

# programmed cell death Apoptosis | The elimination of neurons

Answer 30

* Occurs largely after axons have reached their targets * Noticeable decline in neuron and axon number due to programmed cell death