Transcript Stages in Neuromuscular Synapse Elimination

Synaptic Rearrangement
Objectives:
At the end of this lecture, you should be able to perform the following on a
written examination.
1.
Identify the series of events leading to the elimination of all but one
neuromuscular synapse at developing motor endplates.
2.
Define the salient features of a critical period in developmental
neurobiology. Give examples from the development of the visual system.
3.
Identify the roles played by NMDA receptors and neurotrophins in the
formation of ocular dominance columns.
4.
Compare and contrast the remodeling of synaptic connections in the
visual system and the neuromuscular junction.
Neuromuscular Synapses are Eliminated During
Postnatal Development
At birth, nearly all muscle fibers are
polyneuronally innervated.
During the next two weeks,
all but one of these synaptic
inputs is lost.
Neuromuscular Synapses Compete for Survival
Synchronous electrical activity accelerates elimination, synchronous paralysis
delays it.
• Application of
excesses of different
neurotrophic
molecules prolongs
polyneuronal
innervation
• Several pathways
may exist that help
mediate competition
• Nature of
competition may be
more like a judged
contest than like a
race.
Neuromuscular Synapse Elimination is Gradual
and Asynchronous
Multiple Innervation
Branch Withdrawal
Terminal Segregation
Axon Retraction
Keller-Peck et al, Neuron 31: 381-394, 2001
• Any competition between inputs is
resolved at the level of individual synapses
Synapse Elimination Involves Synaptic Takeover
• The surviving input takes over the synaptic space formerly occupied by the losing
input(s). Walsh & Lichtman, Neuron 37: 67-73, 2003
Synapse Elimination is a Balance of Anterograde
and Retrograde Signals
Proposed Functions of Synapse Elimination
1.
Provides a way to ensure that each muscle fiber is innervated.
2.
Allows axons of different motoneurons to capture a number of cells
appropriate to its size.
3.
Provides a means by which normal function can change the strength of
synaptic connections.
Gatesy & English, Dev. Dyn. 196: 174-182, 1993
• Adult muscles are partitioned into neuromuscular compartments – exclusive innervation
territories.
• In the absence of competition, cross compartmental inputs will form in neonates but not adults
• Synapse elimination completes the specific innervation of neuromuscular compartments
Anatomy of the Visual System
Both eyes project to each visual cortex, but at the primary visual area (17),
they remain largely segregated into ocular dominance columns.
Effects of Neonatal Monocular Deprivation
Normally, most cells receive
visual inputs from both eyes,
but not equally
After MD as neonates, very
few cells receive inputs from
the closed eye
Many cells in visual cortex remain responsive to inputs from both eyes after
binocular deprivation.
•Development of proper circuitry depends on proper balance of inputs from two eyes
Monocular deprivation in adult has no effect
Effects of Monocular Deprivation Are Noted
Anatomically
• Sensory deprivation early in life can alter the structure of the cerebral cortex.
Rudimentary Ocular Dominance Columns Develop in the
Absence of Visual Inputs
• Columns in layer 4a of primary visual
cortex with appropriate eye-specific inputs
are present before the critical period for
ocular dominance column plasticitiy.
•Columns develop in the absence of visual
system input and before the development
of retinal photoreceptors.
• Columns are not altered by visual
deprivation.
Cowley & Katz, Curr. Opin. Neurobiol. 12: 104-109, 2002
• Full development of columns occurs later,
and can be seen as a refinement of these
primitive columns.
Differences from earlier studies is thought to be a matter of technique.
Ocular Dominance Columns are Organized After
Birth
This synaptic rearrangement is
brought about by axon retraction and
local outgrowth of geniculate neurons.
Synchronous Activity From Each Eye Organizes
the Ocular Dominance Columns
Blocking activity in both eyes with TTx or synchronous stimulation of both
optic nerves block formation of ocular dominance columns.
• Asynchronous activity leads to formation of ocular dominance columns.
• Normal development depends on competition for acquisition of synaptic
partners
This competition is emphasized
in three-eyed frogs.
NMDA Receptors Mediate Competition
Cooperative activity of
afferent neurons from
one eye are thought to
depolarize target
neurons sufficiently to
release Mg block of
NMDA receptor, allowing
Ca influx.
NMDA receptor acts as a
coincidence detector of
the activity of neurons
from a single source.
They support one aspect
of the theory of learning
proposed by Hebb.
An additional retrograde signal to the presynaptic neuron is required.
Presynaptic Activity May Enhance Release of
Neurotrophins From Target Neurons
Neurotrophins could form such a retrograde signal.
NGF
trkA
BDNF
NT-4
trkB
NT-3
trkC
p75NTR
NO, another
retrograde signaling
molecule is not
required for formation
of ocular dominance
columns.
Finney & Shatz, J. Neurosci.18: 8826-8838, 1998
Excess of trk B ligands removes the
ability of NMDA receptors to mediate
competition.
Model of Synaptic Rearrangements