Monocular deprivation normally alters ocular dominance in the visual cortex only during a postnatal critical period (20 to 32 days postnatal in mice). We find that mutations in the Nogo-66 receptor (NgR) affect cessation of ocular dominance plasticity.

Visual experience during a critical period early in postnatal development can change connections within mammalian visual cortex. In a kitten at the peak of the critical period (approximately P28-42), brief monocular deprivation can lead to complete dominance by the open eye, an ocular dominance shift. This process is driven by activity from the eyes, and depends on N-methyl-D-aspartate (NMDA) receptor activation. The components of the intracellular signaling cascade underlying these changes have not all been identified. Here we show that inhibition of protein kinase A (PKA) by Rp-8-Cl-cAMPS blocks ocular dominance shifts that occur following monocular deprivation early in the critical period. Inhibition of protein kinase G by Rp-8-Br-PET-cGMPS had no effect, indicating a specificity for the PKA pathway. Enhancement of PKA activity late in the critical period with Sp-8-Cl-cAMPS did not increase plasticity. PKA is a necessary component of the pathway leading to cortical plasticity during the critical period.

Simultaneous recordings from relay cells in the lateral geniculate nucleus (LGN) and their retinal afferents were used to examine the rules governing the transmission of spikes across the retino-geniculate synapse. Retinal spikes that terminate short retinal interspike intervals are much more likely to be transmitted across the synapse than spikes terminating longer intervals. This facilitation can be observed for interspike intervals as long as 50 ms when retinal firing rates are low, but the range of effective intervals decreases exponentially as retinal firing rate increases. Contribution, the fraction of LGN spikes triggered by an individual retinal afferent, is typically much higher during visual stimulation than during maintained activity, and these differences are unrelated to presynaptic or postsynaptic firing rate. It is suggested that this effect is a manifestation of increased synchronization of spikes among retinal afferents to the geniculate cell during structured visual stimulation, and that this synchronization offers a means of enhancing signal-to-noise ratio at the retino-geniculate synapse. Cross-correlograms between geniculate burst spikes and retinal afferents often contain two distinct peaks; a short latency peak that results from direct coupling between burst spikes and retinal input spikes, and a longer latency peak that represents indirect coupling in which retinal spikes trigger the calcium spike underlying the burst. Direct coupling is most likely to occur for the later spikes in the burst, and is present regardless of whether the calcium spike underlying the burst is triggered by the same or a different retinal afferent. These results further illuminate the relationship between tonic and burst modes of retino-geniculate transmission and indicate that bursts in LGN relay cells can be viewed as a mechanism of signal amplification, producing signals whose timing is potentially related to the temporal structure of a stimulus, independent of presynaptic and postsynaptic firing rate. This mechanism also appears to capitalize on the synchronization that is present among parallel retinal afferents to a geniculate cell.

The cAMP-dependent protein kinase (PKA) signaling pathway plays a key role in visual cortical plasticity. Inhibitors that block activation of all PKA regulatory subunits (RI␣, RI␤, RII␣, RII␤) abolish long-term potentiation (LTP) and long-term depression (LTD) in vitro and ocular dominance plasticity (ODP) in vivo. The details of this signaling cascade, however, including the source of PKA signals and which PKA subunits are involved, are unknown. To investigate these issues we have examined LTP, LTD, and ODP in knock-out mice lacking either the two cortically expressed Ca 2ϩ -stimulated adenylyl cyclases (AC1 and AC8) or the predominant neocortical subunit of PKA (RII␤). Here we show that plasticity remains intact in AC1/AC8Ϫ/Ϫ mice, whereas ODP and LTD, but not LTP, are absent in RII␤Ϫ/Ϫ mice. We conclude that (1) plasticity in the visual cortex does not require the activity of known Ca 2ϩ -stimulated adenylyl cyclases, (2) the PKA dependence of ODP and LTD, but not LTP, is mediated by RII␤-PKA, and (3) multiple isoforms of PKA contribute to LTD.

It has been discovered recently that monocular deprivation in young adult mice induces ocular dominance plasticity (ODP). This contradicts the traditional belief that ODP is restricted to a juvenile critical period. However, questions remain. ODP of young adults has been observed only using methods that are indirectly related to vision, and the plasticity of young adults appears diminished in comparison with juveniles. Therefore, we asked whether the newly discovered adult ODP broadly reflects plasticity of visual cortical function and whether it persists into full maturity. Single-unit activity is the standard physiological marker of visual cortical function. Using a more optimized protocol for recording single-units, we find evidence of adult ODP of single-units and show that it is most pronounced in deep cortical layers. Furthermore, using visual evoked potentials (VEP), we find that ODP is equally robust in young adults and mature adults and is observable after just one day of monocular deprivation. Finally, we find that monocular deprivation in adults changes spatial frequency thresholds of the VEP, decreasing the acuity of the deprived pathway and improving the acuity of the non-deprived pathway. Thus, in mice, the primary visual cortex is capable of remarkable adaptation throughout life.

The cAMP-dependent protein kinase (PKA) signalling pathway has been shown to play an important role in long-term potentiation (LTP) and depression (LTD), and ocular dominance plasticity in the visual cortex. In order to investigate further the involvement of individual PKA subunits in visual cortical plasticity, LTP and LTD in vitro and ocular dominance plasticity in vivo in the developing visual cortex were examined in mice lacking the RII alpha subunit of PKA. Here we show that LTP in layers II/III was decreased in RII alpha knockout mice, but LTD was almost unaffected, and the ocular dominance shift induced by monocular deprivation was also partially blocked. These data provide evidence that RII alpha is involved in LTP and ocular dominance plasticity, and further suggest that different afferent inputs could selectively activate particular subunits of PKA and thereby direct specific aspects of visual cortical plasticity.

Mechanisms of plasticity in the visual cortex have been studied with long-term potentiation (LTP), long-term depression (LTD) and ocular dominance plasticity (ODP). It is now possible to compare results from these three forms of plasticity using knockout mice, and also by pharmacological manipulations. A review of the literature shows that if both LTP and LTD are completely abolished, then ODP will also be abolished. In other situations, there is little correlation. We hypothesize that this lack of correlation occurs because the mechanisms for LTP and LTD vary with layer in the visual cortex, and results show that they do.

Numerous protein kinases have been implicated in visual cortex plasticity, but the role of serine/threonine protein phosphatases has not yet been established. Calcineurin, the only known Ca2+/calmodulin-activated protein phosphatase in the brain, has been identified as a molecular constraint on synaptic plasticity in the hippocampus and on memory. Using transgenic mice overexpressing calcineurin inducibly in forebrain neurons, we now provide evidence that calcineurin is also involved in ocular dominance plasticity. A transient increase in calcineurin activity is found to prevent the shift of responsiveness in the visual cortex following monocular deprivation, and this effect is reversible. These results imply that the balance between protein kinases and phosphatases is critical for visual cortex plasticity.