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The regulation of NMDA receptor (NMDAR) subunit composition and expression during development is thought to control the process of thalamocortical afferent innervation, segregation, and plasticity. Thalamocortical synaptic plasticity in the mouse is dependent on NMDARs containing the NR2B subunit, which are the dominant form during the "critical period" window for plasticity. Near the end of the critical period there is a gradual increase in the contribution of NR2A subunits that happens in parallel to changes in NMDAR-mediated current kinetics. However, no extension of the critical period occurs in NR2A knockout mice, despite the fact that NMDA subunit composition and current kinetics remain immature past the end of the critical period. These data suggest that regulation of NMDAR subunit composition is not essential for closing the critical period plasticity window in mouse somatosensory barrel cortex.

Previous anatomic studies of the geniculocortical projection showed that ocular dominance columns emerge by 3 weeks of age in cat visual cortex, but recent optical imaging experiments have revealed a pattern of physiologic eye dominance by the end of the second week of life. We used two methods to search for an anatomic correlate of this early functional ocular dominance pattern. First, retrograde labeling of lateral geniculate nucleus (LGN) inputs to areas of cortex preferentially activated by one eye showed that the geniculocortical projection was already partially segregated by eye at postnatal day 14 (P14). Second, transneuronal label of geniculocortical afferents in flattened sections of cortex after a tracer injection into one eye showed a periodic pattern at P14 but not at P7. In the classic model for the development of ocular dominance columns, initially overlapping geniculocortical afferents segregate by means of an activity-dependent competitive process. Our data are consistent with this model but suggest that ocular dominance column formation begins between P7 and P14, approximately a week earlier than previously believed. The functional and anatomic data also reveal an early developmental bias toward contralateral eye afferents. This initial developmental bias is not consistent with a strictly Hebbian model for geniculocortical afferent segregation. The emergence of ocular dominance columns before the onset of the critical period for visual deprivation also suggests that the mechanisms for ocular dominance column formation may be partially distinct from those mediating plasticity later in life., (Copyright 2001 Wiley-Liss, Inc.)

The mechanisms underlying changes in neural responses and connections in the visual cortex may be studied by occluding one eye during a critical period in early postnatal life. Under these conditions, neurons in the visual cortex rapidly lose their responses to the deprived eye and ultimately lose many of their inputs from that eye. Cats at the peak of the critical period received infusions of exogenous neurotrophin NT-4/5 into primary visual cortex beginning before a short period of monocular deprivation. Within areas affected by NT-4/5, cortical cells remained responsive to the deprived eye, and maps of ocular dominance were no longer evident using intrinsic-signal optical imaging. Cortical cells also became broadly tuned for stimulus orientation and less responsive to visual stimulation through either eye. These effects required at least 48 hr exposure to the neurotrophin and were specific for trkB, because they were not seen with the trkA or trkC ligands NGF or NT-3. Even after neurons had already lost their responses to the deprived eye, subsequent NT-4/5 infusion could restore them. The NT-4/5 effects were not seen after the critical period. Together, these results suggest that trkB activation during the critical period may promote promiscuous connections independent of correlated activity.

Chicken ovalbumin upstream promotor-transcription factor I (COUP-TFI), an orphan member of the nuclear receptor superfamily, is highly expressed in the developing nervous systems. In the cerebral cortex of Coup-tfl mutants, cortical layer IV was absent due to excessive cell death, a consequence of the failure of thalamocortical projections. Moreover, subplate neurons underwent improper differentiation and premature cell death during corticogenesis. Our results indicate that the subplate neuron defects lead to the failure of guidance and innervation of thalamocortical projections. Thus, our findings demonstrate a critical role of the subplate in early corticothalamic connectivity and confirm the importance of afferent innervation for the survival of layer IV neurons. These results also substantiate COUP-TFI as an important regulator of neuronal development and differentiation.

Experimental studies over the past year have shown that neural activity has a range of effects on the development of neural pathways. Although activity appears unimportant for establishing many aspects of the gross morphology and topology of the brain, there are many cases where the presence of neural activity is essential for the formation of a mature system of neural connections; in some instances, the pattern of neural activity actually orchestrates the final arrangement of neural connections.

To investigate the possible anatomical basis for the functional recovery of visual cortical responses after reverse monocular deprivation, we have studied the morphology of single geniculocortical afferents to area 17. In kittens reverse-sutured for 10 d after an initial week of monocular deprivation, single-unit and intrinsic signal optical recordings confirmed that the effects of the initial deprivation were largely reversed. Responses through the originally nondeprived (OND) eye were drastically diminished, but remained much more selective for orientation than after an initial monocular deprivation (Crair et al., 1997). Responses through the originally deprived (OD) eye recovered completely. Geniculocortical afferent arbors in layer IV of area 17 were filled by iontophoresis of Phaseolus lectin into lamina A of the lateral geniculate nucleus (LGN) and were serially reconstructed. Arbors serving both the OD and the OND eye were analyzed. The plastic changes of both OD and OND arbors were evaluated by comparison with arbors reconstructed in normal animals and in animals studied after an equivalent initial period of deprivation (Antonini and Stryker, 1996). These analyses demonstrate that closure of the OND eye caused a substantial shrinkage of the arbors serving that eye. Moreover, reopening the OD eye induced regrowth only in some arbors, whereas others appeared to be largely unaffected and continued to have the characteristics of deprived arbors. Quantitatively, the initial and the second deprivation caused similar proportional changes in total arbor length and numbers of branches, whereas several other features were more severely affected by the initial deprivation.

The role of experience in the development of the cerebral cortex has long been controversial. Patterned visual experience in the cat begins when the eyes open about a week after birth. Cortical maps for orientation and ocular dominance in the primary visual cortex of cats were found to be present by 2 weeks. Early pattern vision appeared unimportant because these cortical maps developed identically until nearly 3 weeks of age, whether or not the eyes were open. The naïve maps were powerfully dominated by the contralateral eye, and experience was needed for responses to the other eye to become strong, a process unlikely to be strictly Hebbian. With continued visual deprivation, responses to both eyes deteriorated, with a time course parallel to the well-known critical period of cortical plasticity. The basic structure of cortical maps is therefore innate, but experience is essential for specific features of these maps, as well as for maintaining the responsiveness and selectivity of cortical neurons.

The significance of functional maps for cortical plasticity was investigated by imaging of intrinsic optical signals together with single-unit recording in kittens. After even a brief period of monocular deprivation during the height of the critical period, only isolated patches of visual cortex continued to respond strongly to the closed eye. These deprived-eye patches were located on the pinwheel center singularities of the orientation map and consisted of neurons that were poorly selective for stimulus orientation. Neurons in regions surrounding the deprived-eye patches responded only weakly to the deprived eye but were well tuned for the same stimulus orientation that optimally excited them when presented to the open, nondeprived eye. The coincidence of deprived-eye patches with pinwheel center singularities, and the selective loss of orientation tuning within the deprived-eye patches, indicate that the orientation and ocular dominance maps are functionally linked and provide compelling evidence that pinwheel center singularities are important for cortical plasticity.

In the primary visual cortex of monkey and cat, ocular dominance and orientation are represented continuously and simultaneously, so that most neighboring neurons respond optimally to visual stimulation of the same eye and orientation. Maps of stimulus orientation are punctuated by singularities referred to as "pinwheel centers," around which all orientations are represented. Given that the orientation map is mostly continuous, orientation singularities are a mathematical necessity unless the map consists of perfectly parallel rows, and there is no evidence that the singularities play a role in normal function or development. We report here that in cats there is a strong tendency for peaks of ocular dominance to lie on the pinwheel center singularities of the orientation map. This relationship predicts but is not predicted by the tendencies, previously reported, for pinwheels to lie near the center lines of ocular dominance bands and for iso-orientation bands to cross ocular dominance boundaries at right angles. The coincidence of ocular dominance peaks with orientation singularities is likely to reflect a strong underlying functional link between the two visual cortical maps.

During development, activity-dependent mechanisms are thought to contribute to the refinement of topographical projections from the thalamus to the cortex. Because activity-dependent increases in synaptic strength may contribute to the stabilization of synaptic connections, we have explored the mechanisms of long-term potentiation (LTP) at thalamocortical synapses in rat somatosensory (barrel) cortex. During early postnatal development (postnatal days 2-5), we find that a significant proportion of thalamocortical synapses are functionally silent and that these are converted to functional synapses during LTP. Silent synapses disappear by postnatal day 8-9, the exact time at which the susceptibility of these synapses to LTP is lost. These findings suggest that the activity-dependent conversion of silent to functional synapses due to correlated pre- and postsynaptic activity may contribute to the early development and refinement of thalamocortical inputs to cortex.

In the CA1 area of the hippocampus, the magnitude of long-term potentiation (LTP) depends not only on the frequency of applied stimuli, but also on their number. With a slice preparation using extracellular recording in the hippocampus CA1 of a guinea pig, we investigate the magnitude of LTP induced by electrical stimuli with a range of frequencies and the number of applied stimuli. We find that the magnitude of the saturated potentiation obtained with periodic stimuli largely depends on the frequency and is insensitive to the number of stimuli, once the saturation level has been obtained. Furthermore, we investigated nonperiodic stimuli and found that the magnitude of the saturated potentiation is also sensitive to the statistical correlation between successive interstimulus intervals, even when their average frequency is held constant. In order to explain the LTP dependence on these various experimental parameters, we propose a simple mathematical model for the induction of LTP. In the model, an exponentially decaying element released as a result of previous stimuli is coupled with a new stimulus to act as the potentiation force, and the magnitude of potentiation is determined by this potentiation force. We can determine the decaying time constant of this hypothetical element as a model parameter by fitting the model to the experimental data. The time scale is found to be of the order of 200 msc. A molecular or cellular factor with this decaying time constant is likely to be induced in LTP induction.

In mammalian development, the refinement of topographical projections from the thalamus to the cortex is thought to arise through an activity-dependent process in which thalamic axons compete for cortical targets. In support of this view, if activity is altered during a critical period in early development, normal connectivity is disrupted. It has been proposed that synaptic connections are strengthened during development by correlated pre- and postsynaptic activity, and a likely mechanism for this process would be N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP). However, the evidence that LTP is involved in normal development remains inconclusive. We have examined LTP in the thalamocortical synapses that form whisker barrels in rat somatosensory cortex (S1). We report here that the period during which LTP can be induced matches closely the critical period during which the barrels can be modified by sensory perturbations. Moreover, the loss of susceptibility to LTP with age is accompanied by a decrease in NMDA receptor-mediated synaptic currents. These findings provide compelling evidence that LTP is important for the development of cortical circuitry.