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How do we know that functional synapses are eliminated
during maturation?
A: Measurement of PSP amplitude after presynaptic
stimulation in developing vs. mature synapses
The postsynaptic potential generated by multiple afferents is
additive
Fewer inputs generate less PSP in mature synapses
Blocking synaptic activity with TTX prevents synapse elimination
at the rat neuromuscular junction
Converse experiment: excess stimulation  precocious synapse
elimination
Rat soleus muscle (leg)/ sciatic nerve
Greater distance between nerve terminals: less elimination
> 2-3 mm: both synapses may survive
1-2 mm: one synapse will be removed
With dual innervation, strong synaptic activity of the 1st depresses
activation of 2nd synapse
2 motor nerve roots:
 less current
Does synaptic depression lead to synapse elimination?
Yes: the AChR blockade experiment
Pharmacological
blockade
Normal
development
Loss of AChRs precedes synapse elimination (live imaging)
reduced AChRs
Red/yellow:
Rhodamine-bungarotoxin
Four mechanisms of synapse elimination during development
Protein kinases A & C (PKA/PKC) mediate activity-dependent
synaptic loss
Postsynaptic Ca2+ depresses synaptic activity, unless
presynaptic cell is stimulated
caged Ca2+ in muscle: UV-stimulated
During development, synapses can be rearranged on target cells
Mammalian retinogeniculocortical (visual) pathway for binocular
vision
In the visual cortex layer IV, LGN terminals are initially mixed,
then resolve
into columns
In the LGN, layers form to segregate RGC inputs, then ocular
dominance columns are generated in cortex
Tracing the cat visual pathway during the first few months
1st segregation occurs at P14
Excessive innervation in the cortex is removed between P22-P92
Covering one eye from 2 wks – 22 mo leads to expanded eyespecific cortical domains in layer IV
Control
Monoculardeprived
Cortical domains=
Ocular dominance
columns
Single-neuron recordings in vivo: the majority of neurons are
binocular (respond to input from both eyes)
Extracellular electrode
Layer IV neurons: monocular
Layers I-III, V-VI: neurons respond to both eyes
If one eye is closed throughout life, it will lose its synaptic
connectivity
*increased loss (closed) + failure to eliminate (open) synapses
No visual input during development does not eradicate ocular
dominance columns or response to visual stimuli
# responsive neurons is much lower than non-deprived controls
*Competition hypothesis: Difference in activity level determines
strength of projection
Deflection of one eye strongly suppresses binocular innervation
*timing of activation must be critical to maintain connectivity
Strabismus also changes intrinsic local cortical projections
Retrograde dye labeling: in strabismic cortex, local
projections to other layers are confined to monocular
columns
*activity-dep refinement within the cortex
Uncorrelated inputs segregate
• Synchronous stimulation of optic nerves
blurs segregation
• Asynchronous stimulation of optic
nerves sharpens segregation
In development of the visual pathway, synaptic refinement occurs
first in the LGN, then in the cortex (IV)
Before light input, RGCs begin firing in waves across retina
Spontaneous waves of RGC activity are lost by P15
Only blockade of neuronal activity ablates formation of columns
*TTX: voltage-gated Na+ channel blocker
Donald Hebb, psychologist (1904-1985)
- The Hebbian theory: synaptic strength
is derived from repeated and persistent
stimulation of a postsynaptic cell by a
presynaptic neuron
Carla Shatz, neurobiologist
“Cells that fire together, wire
together”:
The presynaptic cell must fire first,
and in turn cause the postsynaptic
cell to fire synchronously with other
activating inputs
Synapses are strengthened by synchronous firing on shared target