chapter 9 · fig. 9.10 ocular dominance properties of visual cortex neurons in normally reared...
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© 2019 Elsevier Inc. All rights reserved.
Chapter 9
Refinement of Synaptic Connections
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Fig. 9.1 Three kinds of immature afferent projections. (A) The projection of oneafferent is shown with its arborization centered at the
topographically correct position in the target. However, the arbor initially extends to far, and some of its local branches are eliminated
during development. (B) A single neuron is shown to receive input from three afferents initially, and two of these inputs are eliminated
during development. (C) A projection is shown to innervate the soma and dendrite of a postsynaptic neuron initially, but the somatic
innervation is eliminated during development.
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Fig. 9.2 Functional synapses are eliminated during development. (A) An electrophysiological method for determining the number of inputs
converging onto a neuron. A stimulating electrode is placed on the afferent population while an intracellular recording is obtained from the
postsynaptic cell. As the stimulation current is increased, the afferent inputs are recruited to become active. When a single afferent is
active (top), the postsynaptic potential (PSP) is small. When two (middle), and then three afferents are activated (bottom), the PSP
become quantally larger. One can estimate the number of inputs by counting the number of quantal increases in PSP amplitude, in this
case three. (B) Three examples of decreased convergence as measured electrophysiologically, as described in panel A. On the left are
shown the increases in afferent-evoked PSP amplitude recorded in immature postsynaptic cells of the neuromuscular junction (top), the
chick cochlear nucleus (middle), and the rat autonomic ganglion (bottom). There are 3–5 quantal increases in PSP amplitude. On the right
are shown the increases in afferent-evoked PSP amplitude in mature neurons. There are 1–2 quantal increases in PSP amplitude,
indicating the functional elimination of inputs during development.
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Fig. 9.3 Elimination of commissural axons during development. (A) The schematic shows the location of the anterior commissure, a
bundle of fibers that connect the cortical temporal lobes. (B) Electron micrographs of the anterior commissure of rhesus macaques at two
postnatal ages. There are more axon profiles at P21 than at P90, but myelination is greater at P90. (C) The graph plots the total number
of anterior commissure axons, and the number of myelinated axons, as a function of age. The red and blue dots signify the ages for which
micrographs are shown in panel B. The number of axons reach a maximum at birth, and declines threefold over the next few months.
Myelination begins during this period, but continues for almost 9 months.
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Fig. 9.4 Developmental emergence of specific innervation patterns in the cat visual pathway. (A) When 3H-proline is injected into one eye,
it is transported to the visual thalamus (lateral geniculate nucleus, LGN), and reveals an eye-specific innervation pattern (contralateral
eye, red layers; ipsilateral eye, blue layer). The proline moves transynaptically into thalamic neurons and is transported to the cortex. LGN
neurons project to eye-specific stripes in cortex Layer IV (contralateral eye, red stripes; ipsilateral eye, blue stripes. (B) Images showing
the emergence of eye-specific stripes in the visual cortex. The first column of images (left) shows autoradiograms of 3H-proline in cross
sections. The terminal fields continue to segregate for several weeks of development. The second column of images (right) shows the
activity pattern recorded at the surface of the cortex in response to stimulation of each eye (contralateral, black; ipsilateral, white).
Segregation of afferent can first be observed by about 14 days postnatal.
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Fig. 9.5 Development of retinal ganglion cell terminals in the cat lateral geniculate nucleus (LGN). (A) When individual retinal fibers are
labeled with horseradish peroxidase (HRP) at embryonic days 43–55, they have many side branches in the inappropriate layer of LGN
(arrows). (B) By birth, most of the side branches have been eliminated, and terminals arborizations have been restricted to the correct
layer. However, the terminal zone remains wider in the eye-specific lamina at 3–4 weeks postnatal (arrows). (C) When fibers of retinal
X-cells are filled in adult cats, they are found to have retracted (black arrows).
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Fig. 9.6 Competition and synapse elimination at the neuromuscular junction and at cerebellar Purkinje cells. (A) In vivo imaging of the same multiply
innervated mouse neuromuscular junction from P11 to P14. In these transgenic mice, motor neurons expressed either of two different fluorescent
proteins. One of the motor terminals (blue) occupies a larger percentage of the postsynaptic territory at P11. It gradually withdraws from the junction
(arrows) over the next 4 days, and the other terminal (green) takes over the postsynaptic site. The withdrawing axon is marked by an asterisk at P14.
Scale bar is 10 μm. (B) In vivo imaging of the same two inferior olivary nucleus climbing fibers (CF) innervating a cerebellar Purkinje cell from P11 to
P17. The CFs of a transgenic mouse line expressed enhanced green fluorescent protein (EGFP). A subset of CFs was labeled with a second, red
fluorescent molecule, by injecting the inferior olive with tetramethylrhodamine (TMR). Therefore, all CF fibers fluoresced green, but a subset of axons
could be distinguished because they fluoresced orange (i.e., the combination of green and red). Both CFs innervate a Purkinje cell body at P11.
However, the green CF gradually translocates to the Purkinje cell dendrite by P17, while the orange CF is eliminated. Scale bar is 10 μm. (C) The larger
of two motor axons (orange) innervating a muscle cell is damaged with laser-targeted ablation (circle, arrowhead), and is no longer present by 1 h.
When the same region was imaged 24 h later, the smaller motor axon (green) had come to occupy the entire NMJ. Scale bar is 20 mm. (D) The larger
of two CFs (orange, arrowhead) innervating a Purkinje cell is selectively photo-ablated at P11, and gradually dies away. When the same region is
imaged over the next few days, the smaller CF (green) takes over the Purkinje cell and comes to occupy the dendrite on P15 and P17 (arrowhead).
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Fig. 9.7 Decreased activity prevents synapse elimination. At the rat nerve-muscle junction, polyneuronal innervation declines between 10
and 15 days postnatal (black line). When a TTX cuff is placed around the motor nerve root from postnatal day 9–19 and action potentials
are eliminated, polyneuronal innervation remains high (red circles).
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Fig. 9.8 Increased muscle activity accelerates synapse elimination. Most rat soleus muscles are polyneuronally innervated between
postnatal days 8–10 (black line). When a stimulating electrode is implanted in the leg to activate the sciatic nerve and muscle from
postnatal days 6–8, there is a severe decline in the number of polyneuronally innervated muscle cells (red circles).
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Fig. 9.9 Synapse elimination depends on distance between contacts. Two motor axons were positioned on the same muscle, either close
to one another or at a distance, and intracellular recordings were made to monitor polyneuronal innervation, as shown in Fig. 9.2. When
the synapses are close together (blue circles), synaptic elimination occurs within a few weeks. When the synapses are far apart (red
circles), synaptic elimination fails to occur.
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Fig. 9.10 Ocular dominance properties of visual cortex neurons in normally reared cats. (A) The visual system received normal
stimulation until the time of recording. (B) Single neuron recordings were made with an extracellular electrode that passed tangentially
through the cortex. Neurons respond to only one eye in Layer IV (monocular). In Layers I–III and V–VI, neurons respond to both eyes
(binocular) due to convergent connections. In normal cats, the terminal stripes from each eye-specific layer of the LGN occupy a similar
amount of space. (C) Each neuron was characterized as responding to a single eye (monocular), or responding to both eyes (binocular).
In normal animals, most visual cortical neurons are binocular.
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Fig. 9.11 Thalamic innervation and ocular dominance properties of visual cortex neurons in monocularly deprived cats. (A) The visual
system received normal stimulation through one eye, and the other eye was kept closed until time of recording. (B) The terminal stripes
from the deprived contralateral eye became much narrower (red), and the visual response of neurons outside of Layer IV was more
responsive to the eye that remained open during development (blue). (C) In monocularly deprived cats, the vast majority of cortical
neurons respond to the open eye only (blue).
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Fig. 9.12 Thalamic innervation and ocular dominance properties of visual cortex neurons in binocularly deprived cats. (A) Both eyes were
kept closed until time of recording. (B) The terminal stripes from each eye occupied a similar amount of space. (C) The majority of visually
responsive neurons were driven by both eyes.
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Fig. 9.13 Ocular dominance properties of visual cortex neurons in cats reared with artificial strabismus. (A) One eye is surgically
deflected, such that a visual stimulus activates an inappropriate position on the misaligned eye. That is, individual cortical neurons are not
activated by both eyes at the same time. (B) The terminal stripes from each eye occupied a similar amount of space. However, neurons
outside of Layer IV did not receive convergent input from both eyes. (C) In strabismic cats, the vast majority of cortical neurons responded
to either one eye or the other.
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Fig. 9.14 Visual experience influences intrinsic cortical projections. (A) When a dye injection (green) is made into superficial layers of the
visual cortex of normal cats, the label is retrogradely transported by neurons in ocular dominance columns from both eyes. (B) In cats
reared with artificial strabismus, the label is retrogradely transported only by neurons that share the same ocular dominance.
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Fig. 9.15 Visual experience influences the refinement of retinal ganglion cell (RGC) connections in the Xenopus visual midbrain. (A) The
schematic illustrates that the direction of visual motion will sequentially activate RGCs from posterior to anterior retina. RGC axons form a
topographic map in the optic tectum, with anterior retina projecting to caudal tectum. In this experiment, RGC terminals were labeled with
a fluorescent molecule (tdTomato) and synaptic terminals were identified with fluorescent labeling for Synaptophysin. (B) Tadpoles were
reared in either of two conditions: visual stimuli moved in a biologically normal direction from front to back (left, top) or in an abnormal
direction from back to front (right, top). The rearing stimuli were present for 4 days at 10 h per day. When animals were reared with the
normal direction of motion, the RGC soma position was well-correlated with their appropriately positioned terminals along the rostrocaudal
axis of the tectum (left, bottom). In contrast, when animals were reared in an abnormal direction of motion, the RGC projections did not
refine their terminal arbors properly along the tectum (right, bottom), yielding poor retinotopic maps. (C) A conceptual model of visual
activity-dependent refinement of RGC terminals suggests that small terminal branches are added randomly along the rostrocaudal axis,
but are selectively retracted in an activity-dependent fashion. When two RGC terminals compete, the later activated terminal displays a
selective retraction of rostral branches.
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Fig. 9.16 The sound rearing environment influences tonotopic maps. (A) Developing animals were exposed to a specific acoustic
environment during development. (B) The two lobes of the inferior colliculus (IC) are shown in green, as is the approximate region of the
right auditory cortex (AC). (C) The IC tonotopic map was reorganized when mice were reared in a two-tone environment. Three-
dimensional maps of the inferior colliculus show the region activated by 16 kHz (green) and 40 kHz (red) tones at two postnatal ages, P13
and P19. When animals aged P9–17 were exposed to a synchronous presentation of the two tones, 16 and 40 kHz, a significant volume
of IC became responsive to both rearing frequencies. (D) Representative cortical tonotopic maps from a naïve rat and a rat that had been
exposed to 7.1-kHz tone pulses from P9–30. The average frequency to which each area responded is represented by color. The tone-
exposed animal displayed an expanded region near the rearing tone frequency (green).
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Fig. 9.17 Visual experience influences the alignment of visual and auditory maps in the ban owl midbrain. (A) Immature barn owls were reared with
prismatic goggles that shifted the visual field by 23 degrees. In control animals, a squeaking mouse in front of the owl would appear at 0 degree, and the
sound would reach both ears simultaneously (0 μs interaural time difference, black arrows). With prisms in place, a squeaking mouse at 23 degrees to the
left would appear at 0 degree (blue mouse), but the squeak would reach the left ear first (60 μs interaural time difference, black arrows). (B) A tracer was
injected into the auditory nucleus (ICC, central nucleus of the inferior colliculus) that encodes the ITD of the sound stimulus (left). The IC relays this
information to the ICX where the map of auditory space is assembled. ICX then projects to the optic tectum where visual and auditory information is first
integrated (right). (C) In control animals, the projection from a region in ICC that responds to a 20 μs interaural time difference projects to a narrow region
in the ICX (and ICX then projects to an optic tectal location that responds to visual cues about 8 degrees from the midline). In prism-reared animals, ICC
projected to a more rostral region of ICX. Thus, a new projection is formed within the auditory space map which compensates during prism rearing such
that sound and sight can once again be integrated.
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Fig. 9.18 The visual environment influences orientation and motion processing. (A) Kittens were reared with goggles that permitted visual
experience with only vertically oriented stimuli. The response to oriented stimuli was then obtained from single visual cortex neurons. The cell
shown (middle) responds best to vertical stimuli. In goggle-reared cats, 87% of neurons were selective for vertical stimuli, compared to only
50% in controls. (B) Kittens were reared in stroboscopic light that permitted visual experience, but only with stationary objects. The response to
moving stimuli was then obtained from single visual cortex neurons. The cell shown (middle) responds best to stimuli moving upward. In strobe-
reared cats, only 10% of neurons were motion selective, compared to 66% in controls.
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Fig. 9.19 The selective response of visual cortex neurons to direction of motion emerges after eye opening, and requires visual experience. (A) Stimulus evoked cortical
activity is obtained by monitoring changes in the reflectance of light by the cortex (top). The response of visual cortex to oriented stimuli is shown at two ages, and in a visually
deprived animal (middle). There are already specific responses to vertical (white regions) and horizontal objects (black regions) at the time of eye opening, postnatal day 30
(blue boxes). Specific response to orientation can emerge in the absence of visual experience (dark-rearing). The response of visual cortex to moving stimuli is also shown at
two ages, and in a visually deprived animal (red boxes). There is little response specificity to vertical motion at the time of eye opening, and it emerges over the next several
days. Furthermore, visual deprivation prevents the emergence of direction-specific responses. The graph shows the average amount of response selectivity for orientation
and direction of motion during development (bottom). Orientation selectivity begins to emerge prior to eye opening, and direction-selectivity emerges afterwards. Orientation
selectivity is intact, but somewhat reduced in dark-reared animals (blue square), while direction selectivity is abolished (red circle). (B) Direction selectivity was monitored in
the visual cortex of ferrets that had less than 1 day of visual experience, and moving visuals were presented over the course of several hours. As illustrated by this example,
there was little evidence of direction selectivity in the first 8 h, but strong selectivity began to emerge after 10–12 h of stimulation.
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Fig. 9.20 Spontaneous activity in the developing visual and auditory systems. (A) Retinal explants were obtained from neonatal ferrets and placed on an array
of electrodes to record bursts of spontaneous activity from several retinal locations at the same time (for clarity, only three locations are shown). These bursts of
activity moved across the retina, as shown by the increasing response latency in each oscilloscope trace (left). Electrode array recordings are plotted for mouse
retina from postnatal day 9–15 (right). Each square shows the spatial pattern of activity across the two dimensions of the flattened retinal, with circles
representing individual neurons (circle radius is proportional to firing rate, with a maximum of 20 spikes/sec). By P15, the spontaneous activity no longer travels
across the retina. The spatial activity patterns were acquired every 4 s. (B) Spontaneous retinal waves drive activity in the superior colliculus (SC) and visual
cortex (V1). Wide-field calcium imaging was used to measure fluorescence from a calcium indicator dye in both the SC and V1 (left). A sequence of images is
shown for a P9 mouse (right), and the white numbers show time in seconds. Retinal-driven activity progresses across both the SC and V1 (arrows). (C) The
cochlea is removed prior to the onset of hearing and placed in vitro to visualize inner hair cells (IHC) and auditory neurons (AN). The schematic illustrates that
supporting cells release ATP which leads to the activation of adjacent IHCs. (D) Recordings obtained simultaneously from an IHC (blue trace) and a nearby AN
fiber (black trace) displayed a correlated bursting response (left). When an antagonist of ATP receptors was added to the bath, spontaneous activity was
eliminated (right).
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Fig. 9.21 Spontaneous activity in the developing cortex. (A) Hindlimb twitching during sleep drives activity in motor cortex (M1).
Recordings were obtained from M1 of anaesthetized rats at P8–10 as they cycled between sleep and waking states. The activity of leg
muscles was monitored with an electromyogram (EMG). While animals were awake, the hindlimbs moved freely (red line) and EMG
activity was continuous, but little activity was recorded in M1. In contrast, when animals were asleep, the hindlimbs twitched (red tick
marks), there were brief bouts of EMG activity, and M1 was very high. The histogram of M1 activity (right) shows that discharge rate
increased immediately after each twitch. (B) Brain slices were obtained from rats during the first postnatal week, and intracellular calcium
was monitored using a Ca-sensitive indicator (top). Waves of spontaneous activity swept across the cortex from caudal to rostral (bottom).
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Fig. 9.22 Spontaneous retinal activity regulates the formation of stripes. (A) Cats were reared in the dark, and 3H-proline was injected into
one eye to visualize ocular dominance columns. Although the columns were slightly degraded, they did form. (B) Bilateral intraocular TTX
injections were performed beginning at postnatal day 14. When 3H-proline was injected into one eye to visualize ocular dominance
columns, it was found that segregation of geniculate afferents into stripes failed to occur. Thus, spontaneous retinal activity is sufficient to
influence stripe formation.
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Fig. 9.23 Critical periods for the effects of monocular deprivation. One eye was sutured shut in macaque monkeys at different postnatal
ages. The sutures were removed after several months, and ocular dominance columns were examined with anatomical (left) and
electrophysiological techniques (right). When deprivation began between 0 and 2 months of age, most neurons subsequently responded
to the open eye only, and the open eye occupied much more of Layer IV. The effects of deprivation declined with age. The anatomical
effect of deprivation on ocular dominance columns declined more rapidly than the physiological effect on ocular dominance histograms.
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Fig. 9.24 Synaptic inhibition regulates the critical period for ocular dominance plasticity. (A) In normal mice, recordings from the binocular
region of visual cortex (top) yield an ocular dominance histogram that is biased towards the contralateral eye (bottom left). When juvenile
mice were monocularly deprived (MD) between 19–32 days, the ocular dominance histogram was shifted towards the nondeprived eye
(bottom right, blue-shaded bars). The distribution of cells in the control histogram is shown for comparison (dashed line). (B) When adult
animals were monocularly deprived, there was no change to the ocular dominance histogram. In contrast, mice lacking the GABA-
synthesizing enzyme, GAD65, continued to display an effect of MD. (C) Embryonic inhibitory neurons can be obtained from their zone of
proliferation (top), the medial ganglionic eminence (MGE), and transplanted into the visual cortex at P10 (bottom). These animals also
continued to display an effect of MD after the normal critical period ended.
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Fig. 9.25 NMDA receptors mediate developmental plasticity. (A) The NMDA receptor is activated by a combination of glutamate binding and
membrane depolarization. A positively charged magnesium ion blocks the NMDA receptor channel at rest. Depolarization causes the
magnesium ion to be ejected, and this permits sodium and calcium ions to flow in. (B) When a third eye was implanted into a frog embryo, the
tectum became coinnervated by two eyes. The afferents from each eye segregated into stripes (top left). An image of the dorsal surface of the
tectum shows the pattern of innervation when the retinal ganglion cell afferents from one eye were labeled (bottom left). When three-eyed frogs
were treated with a NMDAR antagonist, the afferents did not segregate, and stripe formation was prevented (middle). When three-eyed frogs
were treated with NMDA, stripe formation was enhanced (right), and the border between stripes became sharper.
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Fig. 9.26 Heterosynaptic depression at the developing neuromuscular synapse in vivo and vitro. (A) The lumbrical muscle in the rat foot is innervated by
two physically separate motor nerve roots, LP and SN. In control animals, stimulation of the SN motor nerve root (red) elicits a robust contraction of the
lumbrical muscle (left). However, when the LP motor nerve root (blue) was repetitively stimulated during the developmental period when synapse
elimination occurs, then SN nerve root stimulation elicited a much weaker contraction of the lumbrical muscle (right) when it is subsequently tested.
Therefore, stimulation of one set of synapses leads to a decrease in the strength of a second set of synapses, referred to as heterosynaptic depression.
(B) Whole-cell recordings were made from Xenopus muscle cells that were coinnervated by two neurons (left). Evoked synaptic currents were first
measured in response to stimulation of each neuron (top left). A strong stimulus was then applied to neuron 2 (blue), and the strength of each neuron
tested again. Stimulation of neuron 2 led to smaller evoked synaptic currents from the unstimulated neuron 1 (red) but did not change the neuron 2-
evoked response (top right). The graph of ESC amplitude before and after stimulation of neuron 2 shows that the depression was long-lasting (bottom
right).
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Fig. 9.27 Transient expression of long-term depression may mediate synapse elimination (A) Long-term depression (LTD) declines with age in Layer IV of visual
cortex. At postnatal day 6, low-frequency stimulation of the thalamic afferents induced long-lasting depression of excitatory synaptic currents. By P90, the same
treatment has no effect. The probability of detecting LTD is nearly 90% in tissue from juvenile animals but is negligible in young adults. (B) Contacts between
presynaptic terminals (red) and postsynaptic spines (green) were monitored before and after the induction of LTD in a hippocampal slice (top). The presynaptic
contact withdrew following LTD induction. When this experiment was repeated many times, it was found that those synapses displaying the greatest depression were
associated with a decrease in colocalization of pre- and postsynaptic elements (red shading, bottom left). In contrast, those synapses displaying the greatest stability
of response were equally likely to increase their colocalization (green shading, top right). (C) LTD was impaired in animals lacking major histocompatibility class I
(MHCI) proteins. Optically evoked LTD is ordinarily observed at retinogeniculate synapses in wild-type (WT) mice. However, when two MHCI genes were deleted
(KbDb −/−), the LTD was eliminated. (D) During normal development, ipsilateral retinal ganglion cell (RGC) projections to the lateral geniculate nucleus (LGN) initially
innervate territory belonging to the contralateral eye and are subsequently eliminated (top). Images show ipsilateral (green) and contralateral (red) RGC projections
to the LGN in WT mice, and those missing two MHCI genes (KbDb −/−). The ipsilateral projection failed to complete its normal period of elimination and refinement in
KbDb −/− mice.
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Fig. 9.28 Synapse depression depends on postsynaptic calcium. (A) A whole-cell recording was made from an innervated muscle cell
that was filled with “caged” calcium. Intracellular calcium is elevated when UV light releases the calcium from its “cage” (left). Under these
conditions, nerve-evoked synaptic currents became depressed (middle). Baseline nerve-evoked synaptic currents were recorded from the
muscle cell during a control period (black downward deflections beneath each dot which represent the stimuli). When intracellular calcium
was elevated by exposure to UV light, the nerve-evoked synaptic currents (red) became depressed within seconds. This suggests a
model in which elevated calcium triggers the release of a retrograde factor that leads to reduced presynaptic transmitter release (right).
(B) When the presynaptic nerve was stimulated during the UV-evoked rise in calcium (left), synaptic depression was prevented (middle).
In this case, the model suggests that presynaptic activity can interfere with the retrograde signal (right).
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Fig. 9.29 Heterosynaptic depression is associated with a loss of postsynaptic AChRs. (A) The schematic shows muscle cells that are coinnervated by
two neurons in vitro. When one neuron is stimulated for 1–2 h, the nonstimulated neuron displays heterosynaptic depression and a loss of AChRs (red)
beneath its synapse. The images show staining for nerve (green) and AChR clusters (red) beneath the unstimulated synapse before (left) and after
(right) heterosynaptic depression. AChR aggregates are stained with rhodamine-bungarotoxin. (B) Model of activity-dependent synapse elimination. The
active terminal increases PKA and PKC locally. PKC phosphorylates AChRs beneath the inactive terminal, leading to their loss. However, PKA activity
can protect the AChRs beneath the active terminal. PKC may become activated by calcium influx, whereas PKA may become activated by a ligand that
is released along with ACh. (C) Synapse elimination is induced by proBDNF. Immunostaining of the nerve-muscle junction reveals axons and terminals
(green) and postsynaptic AChR clusters (red). At postnatal day 6, the nerve terminals were induced to retract during the in vivo application of proBDNF.
(D) A model of synapse elimination suggests that postsynaptic release of proBDNF can act through its receptor complex (p75NTR and sortillin) on
presynaptic terminals to induce elimination. However, when proBDNF is proteolytically converted, the mature BDNF can act via its receptor (TrkB) to
stabilize presynaptic terminals.
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Fig. 9.30 Activity-dependent synapse formation and cell adhesion molecules. (A) In wild-type flies (left), muscles 6 and 7 receive about
180 boutons, and the expression of FasII (blue) is relatively high. In an eag Shaker mutant strain of flies (right) with increased activity,
FasII levels are lower and about 70% more boutonal endings are formed. (B) A model illustrates that synaptic activity leads to calcium
influx and activation of the kinase, CaMKII (left). The active CaMKII phosphorylates a protein that mediates clustering of synaptic proteins
(DLG), including the cell adhesion molecule, FasII. The phosphorylated DLG is not as restricted to the synaptic complex, and FasII may
no longer be located at the synapses, leading to less adhesion and sprouting of new boutons (right). Synaptic sprouting is induced by
Glass bottom boat (Gbb), a TGF-β/BMP ligand, via an interaction with a presynaptic TGF-β receptor, Wishful thinking (Wit).
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Fig. 9.31 GABA transmission is required for normal inhibitory synapse formation. The axonal projections of cortical inhibitory neurons was
analyzed in control mice, and compared to animals in which the GABA synthesizing enzyme, GAD67, was inactivated. The axonal
projections (green) of control inhibitory cells (top left) were much denser compared to those in GAD67 −/− mice (bottom left). On average,
the control axons targeted about twice as many postsynaptic cell bodies. The number of inhibitory terminal boutons per postsynaptic
pyramidal cell also declined by about 50%.
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Fig. 9.32 Activity-dependent elimination of inhibitory connections during development. (A) Animals can locate a sound source based on the sound intensity
difference between the two ears (top). A nucleus in the auditory brainstem, the lateral superior olive (LSO), encodes intensity differences by integrating
excitatory input driven by the ipsilateral ear with inhibition driven by the contralateral ear (bottom). This inhibition is mediated by MNTB neurons which map
tonotopically onto the LSO. (B) The development of two MNTB arbors is shown schematically (top). During the period prior to hearing, the number of functional
connections between MNTB and LSO decreases dramatically (P13 control, dashed lines). During the period after hearing onset, MNTB axonal arbors are
eliminated anatomically (P21 control). The anatomical elimination was assessed by measuring individual MNTB terminals arbors and presynaptic boutons at
each age (bottom). In AChR α9 knockout mice, the spontaneous activity pattern is altered, but the absolute amount of activity remains unchanged. This
manipulation had no effect on MNTB innervation through P13, but interfered with the anatomical refinement of MNTB terminals during the third postnatal week.
(C) MNTB terminals are also eliminated in a second postsynaptic target, the MSO. At birth, inhibitory terminals are located on the soma and dendrites of MSO
neurons. However, most of the dendritic synapses are eliminated during postnatal development (top left). The micrograph (top right) shows stained MSO
neurons and glycine receptors from an adult animal. The glycine receptors (yellow) are largely restricted to the soma, and very few remain on the dendrites
(blue). When animals were deafened unilaterally during development, the elimination of inhibitory synapses failed to occur (bottom left). The micrograph shows
that, following deafening, significant glycine receptor staining (yellow) remained on the dendrites (bottom right). Scale bars are 20 μm.
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Fig. 9.33 Homeostatic plasticity of excitatory and inhibitory synapse function in the developing auditory cortex. (A) The schematic shows the orientation
of a brain slice containing the project from auditory thalamus (MG) to auditory cortex (ACx). Stimuli delivered to the MG activate excitatory afferents
(green) and excitatory synaptic currents can be recorded in the ACx. Stimuli delivered within the ACx activate inhibitory afferents (red) and inhibitory
synaptic currents can be recorded. (B) A comparison is made between evoked synaptic currents in control animals (Ctl) and those raised with bilateral
hearing loss (HL). Electrical stimuli are delivered just above threshold to activate a single excitatory or inhibitory afferent. The traces and bar graph
illustrate that developmental HL induced an increase in the amplitude of evoked excitatory synaptic currents (green), yet caused a decrease in the
amplitude of inhibitory currents (red). (C) To determine whether the onset of visual experience influences auditory cortex development, the eyelids were
either opened prematurely (left) or eyelid opening was delayed (right). Normal eyelid opening occurs at ~ postnatal day 18 in gerbils. (D) The effect of
eyelid opening was tested by determining whether the auditory cortex remained vulnerable to hearing loss induced with bilateral earplugs. When the
eyelids were opened prematurely, the auditory cortex lost its sensitivity to hearing loss by P15. However, when the eyelids were glued shut, the auditory
cortex remained vulnerable to hearing loss through P19, after the critical period would ordinarily have closed.
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Fig. 9.34 Increased auditory activity during development influences cortical vascular development. When mice were reared with 10 h of
daily auditory stimulation from P15 to 25, there was a significant reduction of blood vessels in auditory cortex (A1). (A) The images show
the microvasculature in A1 of sound-reared and control mice. The blood vessels were visualized with an immunohistochemical stain for
collagen IV. (B) The vasculature was quantified by measuring blood vessel branch points. A significant reduction was observed in A1
animals exposed to sound from P15–25. However, blood vessels in a control region, the cingulate cortex, were not affected. Furthermore,
when 9-week old adults were exposed to the same treatment, the A1 vasculature was not affected. Scale bar, 200 μm.
© 2019 Elsevier Inc. All rights reserved. 36
Fig. 9.35 Synaptic activity regulates dendrite morphology. (A) Neurons of the chick nucleus laminaris (NL) receive afferents from
ipsilateral NM to their dorsal dendrites and from the contralateral NM to their ventral dendrites (left). The ventral dendrites of NL neurons
were denervated by cutting NM afferent axons at the midline. The dorsal dendrites remained fully innervated. When NL neurons were
stained with the Golgi technique, the ventral dendrites were found to be significantly shorter than those on the dorsal side (right). (B) The
ventral dendrites shrunk by almost 40% by 96 h after the lesion, and this effect can be measured within 1 h of the manipulation. (C) Two-
photon imaging of dendritic spine and filopodia motility in vivo shows the age-dependent effect of visual deprivation. Two time-lapse
sequences are shown (acquired over 2 h). In the first, a spine retracts (top), and in the second a spine elongates (bottom). (D) Binocular
deprivation from P13 significantly increases spine motility at P28 by 60%. However, there is no change in motility when animals are
imaged at P21, and only a slight reduction in motility in mice imaged at P42.
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