LECTURE
Developmental changes and ocular dominance plasticity
in the visual cortex
Nigel W. Daw and Christopher J. Beaver
Department of Ophthalmology and Visual Science, Yale University Medical School, New Haven, CT, USA(Received for publication on March 19, 2001)

Abstract. There is a shift in ocular dominance of cells recorded in the visual cortex which occurs after
closure of one eye during a critical period lasting from eye opening to puberty. Three criteria distinguish factors that are crucially related to ocular dominance plasticity: 1) the factor should be moreconcentrated or active at the peak of the critical period; 2) dark rearing, which makes the cortex lessplastic early in the critical period and more plastic late in the critical period, should have a similar effecton the factor, and 3) antagonists or inhibitors of the factor should block ocular dominance plasticity.
The second criterion can be used to distinguish activity-related factors that may simply increase or decrease with development from factors that are more speci®cally related to plasticity. Two factors currently ful®ll these criteria, namely N-methyl-D-asparate (NMDA) receptors and protein kinase A(PKA). PKA and NMDA receptors are linked through calcium, since calcium in¯ux through the
NMDA receptor increases the production of cyclic AMP by calcium-sensitive adenylate cyclase, which
in turn activates PKA. PKA is speci®cally involved, since protein kinase G and protein kinase C
antagonists do not inhibit ocular dominance plasticity. However, NMDA agonists and PKA activators
by themselves are not known to bring back plasticity. Thus there may be two or more pathways forocular dominance plasticity acting in parallel with each other: for example, metabotropic glutamate
receptors may act in parallel with NMDA receptors to change calcium levels within the cell. (Keio J
Med 50 (3): 192±197, September 2001)
Key words: plasticity, NMDA, cAMP, protein kinase A, visual cortex

Introduction
Connections in the visual cortex can be modi®ed byvisual experience early in life. This is a means to compensate for ocular or motor defects, such as when theeyes point in different directions (strabismus), one eye
is out of focus (anisometropia), or one or both eyes
have a cataract (stimulus deprivation). The mechanismof compensation is that vision in one eye is suppressed
and/or loses acuity.
The anatomical and physiological effects involved
are now quite clearly understood from experiments inanimals using monocular deprivation, where the eyelidsof one eye are closed for a period of time. Connections
from the deprived eye decay,1,2 and the percentage ofcells in the visual cortex that can be driven by thedeprived eye is reduced,3 so that after substantial deprivation, the animal becomes blind in that eye.4 The
current question of interest is: how does the afferent
activity reaching the cortex from the two eyes lead tothe decay of connections and synapses between the
deprived eye and cortical cells, and to the expansion ofconnections from the non-deprived eye? What are theintermediate steps?
There are three criteria for a factor that is closely
related to ocular dominance plasticity. The ®rst is thatthe concentration or activity of the factor should follow
the critical period for ocular dominance plasticity. The
critical period starts after eye opening, and ends around
puberty. In the cat, which is the animal used for mostof our experiments, it starts around 3 weeks of age, ismost sensitive at 4±6 weeks of age, and ends around 9

Presented at the 1199th Meeting of The Keio Medical Society in Tokyo, February 28, 2001.
Reprint requests to: Dr. Nigel Daw, Department of Ophthalmology and Visual Science, Yale University Medical School, New Haven,
CT 06520-8061, USA, e-mail: nigel.daw@yale.edu
192

Keio J Med 2001; 50 (3): 192±197

months of age.5±8 At the peak of the critical period,
monocular deprivation for a day or two has an effect.
The second criterion is that rearing in the dark should
affect plasticity and the factor in a similar fashion.
Rearing in the dark is known to increase plasticity laterin the critical period,9 and to reduce it early in the critical period.10 Thus 5±6 week old dark-reared cats areless plastic than normal, 8±9 weeks old dark-reared cats
are equally plastic, and 12±20 week old dark-rearedcats are more plastic than normal. This second criterion
is particularly important, because it distinguishes factors related to activity, which simply increases with age,from factors related to plasticity.
The third criterion is that antagonists or blockers of
the factor should reduce or abolish plasticity. The mostcommon experiment is to measure the ocular dominanceof a sample of cells in the visual cortex, and construct anocular dominance histogram, which is shifted from normal by monocular deprivation.3 Numerous treatments
have been shown to reduce this ocular dominance shift.
The list includes N-methyl-D-aspartate (NMDA) receptor antagonists,11,12 protein kinase A (PKA) antagonists,13 depletion of noradrenaline and acetylcholine,14
and infusion of growth factor compounds,15,16 or class I
MHC antigens17 inter alia. Very few treatments block
the ocular dominance shift altogether, one of the few
being tetrodotoxin, infused so that it blocks the afferent
activity from the retina.18 However, at the present time,
there are only two factors known to ful®ll all three ofthe criteria listed above, NMDA receptors and protein
kinase A. This article will summarize the evidence inrelation to these two factors.
NMDA Receptors
NMDA receptors were an early candidate as a factor
involved in plasticity, because they are ligand-gated byglutamate, and also voltage sensitive.19,20 The voltage
sensitivity of NMDA receptors on a postsynaptic cellincreases the probability that the cell will ®re when thepresynaptic cell ®res. This increases plasticity according
to Hebb's postulate that simultaneous ®ring of pre- andpostsynaptic cells will strengthen the synapse in between.21
We have shown that Bmax for NMDA receptors in
the visual cortex follow the critical period for plasticity
in the visual cortex (Fig. 1).22 There is also a drop in
the NMDA contribution to the visual response in layers
IV, V and VI,23 which occurs at the same time as theafferents from the lateral geniculate to the cortex aresegregating into bands for the left and right eyes. The
drop in this NMDA contribution is delayed by rearing
in the dark,24 just as ocular dominance segregation isdelayed by rearing in the dark.25
The NMDA antagonist amino phosphonobutyric

193

Fig. 1 NMDA receptor binding to membranes from cat visual cortex
follows the critical period for ocular dominance plasticity in cat visualcortex.

acid (APV) reduces ocular L-dominance plasticity.11,26
This experiment was criticized on the grounds that APV
might reduce activity suf®ciently that it would be justlike TTX, which would change the interpretation of theexperiment.27 We therefore repeated the experimentusing the NMDA channel blocker, ()-5-methyl-10,11dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801). We found that this drug, injected
into the leg muscle, reduced ocular dominance plasticity at a dose of 0.1 mg/kg (Fig. 2).12 This dose abolishes the response to NMDA in the visual cortex,
without affecting the visual response, or the responsetoa-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) (Fig. 3). Higher doses of MK801 may
affect the visual response, but there is a dose that
affects plasticity with little effect on activity. A similar
result has been obtained using antisense oligonucleotides for NMDA receptors.28 Thus NMDA receptors
ful®ll the three criteria listed above for a factor speci®cally related to ocular dominance plasticity in the visualcortex.
Protein Kinases
Several protein kinases have been implicated inplasticity in the hippocampus. This includes PKA,29,30
protein kinase C (PKC),31 and protein kinase G(PKG).32,33 PKA has also been implicated in learning
in Drosophila.34
PKA is activated by cyclic AMP (cAMP), and levelsof cAMP produced by the metabotropic glutamate
agonist ACPD in the visual cortex follow the critical
period closely (Fig. 4).35 This is primarily due to developmental changes in levels of cAMP up to the age of 15
weeks, while the drop to zero between 15 weeks andadult is due to the drop in metabotropic glutamate
receptors.36 Levels of cAMP are lower than normal in 5

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Fig. 2 Ocular dominance histograms from cats monocularly deprived(MD) for 5 days at 4±5 weeks of age (top) showing a shift towards theopen eye, compared with MD cats treated with injections of 0.1 mg/kg
MK-801 in the muscle twice daily. The MK-801 reduced the oculardominance shift.

week dark-reared animals, similar to normal at 9 weeks
of age, and higher than normal at 15 weeks of age,35
just as ocular dominance plasticity is less than normal,
equal to, and greater than normal at these ages.10
We have also found that inhibitors of PKA reduce
ocular dominance shifts suf®ciently that they are almost
totally blocked (Fig. 5).13 This result is also obtained
without having a signi®cant effect on visual responses
or signal/noise ratio in the visual cortex. However, ocular dominance shifts are not reduced or blocked byinhibitors of PKG or inhibitors of PKC (Fig. 5). The
result with inhibitors of PKG agrees with previous
results, showing that inhibitors of nitric oxide synthasealso do not affect ocular dominance shifts (nitric oxide
produces cGMP, which activates PKG).37,38 Thus there
is a distinct difference between plasticity in the visualcortex and plasticity in the hippocampus as far as therole of protein kinases is concerned.

Daw NW and Beaver CJ: Ocular dominance plasticity in visual cortex

Fig. 3 A 0.1 mg/kg injection of MK-801 abolishes the response toiontophoresis of NMDA in the visual cortex, with little effect on thevisual response, or the response to iontophoresis of AMPA.

Fig. 4 Levels of cAMP produced by the general metabotropic glutamate agonist, ACPD, in the cat visual cortex, follow the critical
period for ocular dominance plasticity closely. Levels are lower in
dark-reared animals at 5 weeks of age, and higher in dark-rearedanimals at 15 weeks of age.

Keio J Med 2001; 50 (3): 192±197

195

stores. We found that MK801, at doses that did notaffect the visual response, reduced the ocular dominance shift but did not block it altogether. This suggeststhat other routes to change in calcium concentration
may also play a role. On the other hand, PKA antagonists did block the ocular dominance shift totally. Thisis consistent with our observation that antagonists toother protein kinases did not affect the ocular dominance shifts. Levels of calcium and cAMP may be apoint in the biochemical pathways for ocular dominance plasticity where signals converge, as has beensuggested for plasticity in the hippocampus.40
Summary and Future Directions

Fig. 5 Ocular dominance shift in 25±31d cats monocularly deprived
for 5 days (top left). Infusion of a PKA inhibitor (Rp-8-Cl-cAMPS
at 20 mM from an Alzet osmotic minipump) blocks the ocular dominance shift (right). Infusion of a PKG inhibitor (Rp-8-Br-PETcGMPS at 1 mM) does not (middle left), nor does infusion of a PKC
inhibitor (either chelerythrine chloride at 166 : M, or an inhibitory
myristolated peptide at 4 mM ± see bottom left).

Restoration of Plasticity
All of these results lead to the following hypothesis:that activity coming from the two eyes releases glutamate in the cortex, which activates NMDA receptors,
which lets calcium into the cell, which activates calciumstimulated adenylate cyclase, which produces cAMP,
which activates PKA and leads to protein synthesis forthe degradation of some synapses and the formation ofothers. If this simple hypothesis were true, then application of a PKA agonist or an NMDA receptor agonist
late in the critical period might accentuate plasticity.
This result has been found to be not true in our laboratory with application of the agonist Sp-8-Cl-cAMPS
at 15 weeks of age.13 Other authors have seen a change
in binocularity, although not a shift from one eye tothe other, with application of forskolin and dibutyrylcAMP, which both activate PKA.39 The experimenthas not been tried with agonists acting at the NMDA
receptor.
There are several reasons why restoration of plasticity might be dif®cult. It may not be suf®cient simply toactivate all PKAs or all NMDA receptors: the PKAs or
NMDA receptors might have to be activated at thecorrect place at the correct time. Moreover, there may
be pathways acting in parallel with each other. For example, NMDA receptors and voltage-gated calcium
channels both let calcium into the cell, and metabotropic glutamate receptors release it from intracellular

In summary, we have shown that both NMDA
receptors and levels of cAMP produced by metabotropic glutamate receptors follow the critical period forocular dominance plasticity in the cat visual cortex
closely. Rearing in the dark affects these substances,as it does ocular dominance plasticity. Antagonists to
NMDA receptors reduce ocular dominance plasticity
while antagonists to the protein kinase activated bycAMP, protein kinase A, block ocular dominance plasticity altogether. We suggest from this that various
receptors and channels converge to affect calcium in thecell, and calcium in turn affects cAMP. If this is true,
then the calcium-stimulated adenylate cyclases, AC1
and AC8, which are found primarily in the brain,
should also be a crucial factor that will block oculardominance plasticity totally, rather than just reduce it.
We are currently testing this with double mutants of
AC1 and AC8 kindly provided by Dr Daniel Storm.
The next question is: how does activation of PKA
lead to protein synthesis for degradation of some synapses and production of others? This is an importantquestion where research is just starting to make a contribution. PKA is known to have both immediate andlong-term actions on synaptic function. In the shortterm, PKA can up or down-regulate the activity of both
excitatory and inhibitory neurotransmitter receptors
through direct interactions.41,42 In the longer term,
PKA is likely to modulate the expression of speci®cgenes by directly controlling the activity of transcription
factors such as the calcium/cAMP response elementbinding protein (CREB).43 Alternately, PKA could
control gene transcription by acting through the phosphorylation of other kinases such as the mitogen-activated protein kinases that have been shown to control
gene expression44 and that have been implicated insynaptic plasticity in other regions of the brain.45,46 Indeed, there is evidence that CREB-mediated genetranscription in the visual cortex of CRE-lacZ transgenic mice is upregulated by periods of monoculardeprivation.47 Beyond that, not much is known. The

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Daw NW and Beaver CJ: Ocular dominance plasticity in visual cortex®eld is currently an exciting one, because it has relevance to clinical problems, is relevant to plasticity inother parts of the nervous system, and is being done ina system where behavior, anatomy, and physiology canbe correlated. While much has been done, there areclearly a lot of open questions.

18.

Acknowledgements: This work was supported by National Institutesof Health grants EY00053 and EY11353. Nigel Daw is a Senior Scienti®c Investigator of Research to Prevent Blindness.

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