Experience-Dependent Plasticity and the Maturation of Glutamatergic Synapses
Authors: Daniel E Feldman, Eric I Knudsen
Journal: Neuron (1998)

Glutamatergic synaptic currents undergo a characteristic pattern of maturation during early development. This pattern involves changes in the kinetics of N-methyl-D-aspartate (NMDA) receptor currents and, possibly, the formation of "silent" synapses that express only NMDA receptor currents and are later made functional by the addition of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptor currents. These maturational changes in glutamatergic synapses have implications for the early development of neural networks (6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar) and for the mechanisms underlying long-term potentiation (LTP) of synaptic efficacy (29Malenka R.C Nicoll R.A Silent synapses speak up.Neuron. 1997; 19: 473-476Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Here, we suggest that this pattern of synaptic maturation also has important implications for understanding how already functional networks are adaptively modified by the experience of the individual animal during later stages of development and possibly into adulthood. Early in development, functional circuits are established by axonal pathfinding, target selection, synaptogenesis, and activity-dependent refinement of synaptic connections. Later in development, these initial circuits may undergo extensive adaptive modification by sensory and motor experience. This late developmental period occurs while the animal is a juvenile, after basic neural circuits are established and functioning but before the onset of sexual maturity. This juvenile period is marked by a high capacity for learning (24Konishi M Birdsong for neurobiologists.Neuron. 1989; 3: 541-549Abstract Full Text PDF PubMed Scopus (82) Google Scholar, 26Kuhl P.K Learning and representation in speech and language.Curr. Opin. Neurobiol. 1994; 4: 812-822Crossref PubMed Scopus (176) Google Scholar, 4Brainard M.S Knudsen E.I Sensitive periods for visual calibration of the auditory space map in the barn owl optic tectum.J. Neurosci. 1998; 18: 3929-3942Crossref PubMed Google Scholar). The neural basis for this learning is experience-dependent modification of neural circuitry that can involve changes in both the efficacy of existing synapses and the patterning of anatomical connections. Increasing evidence demonstrates that experience-dependent changes in anatomical connectivity can be substantial during late development (11Feldman D.E Knudsen E.I An anatomical basis for visual calibration of the auditory space map in the barn owl's midbrain.J. Neurosci. 1997; 17: 6820-6837PubMed Google Scholar) and even in adulthood (e.g., Bailey and Kandel, 1983; 8Darian-Smith C Gilbert C.D Axonal sprouting accompanies functional reorganization in adult cat striate cortex.Nature. 1994; 368: 737-740Crossref PubMed Scopus (520) Google Scholar, 15Florence S.L Kaas J.H Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys.J. Neurosci. 1995; 15: 8083-8095Crossref PubMed Google Scholar). Because such anatomical changes involve the formation of new synapses, understanding the maturation of synaptic transmission at newly formed synapses may provide important insight into how experience modifies already functioning neural circuits. In this review, we discuss our current understanding of the maturation of glutamatergic transmission in early development, and we apply these principles to propose a general model for the role of NMDA receptors and the maturation of glutamatergic synapses in experience-dependent modification of neural circuits. The majority of fast excitatory neurotransmission in the CNS is mediated by ionotropic glutamate receptors, which are divided into NMDA, AMPA, and kainate receptor subtypes on the basis of the biophysical properties of their currents, their sensitivity to different pharmacological agents, and the classification of their subunits into distinct genetic families. Both AMPA and NMDA receptors are usually colocalized at individual synapses, so that the synaptic release of glutamate typically activates both AMPA and NMDA receptor currents on the postsynaptic neuron (33Nicoll R.A Malenka R.C Kauer J.A Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system.Physiol. Rev. 1990; 70: 513-565Crossref PubMed Scopus (672) Google Scholar). However, the ratio of AMPA to NMDA currents at a given synapse depends on the identity and maturational stage of the synapse (e.g.,19Hestrin S Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse.Nature. 1992; 357: 686-689Crossref PubMed Scopus (458) Google Scholar, 32Mooney R Synaptic basis for developmental plasticity in a birdsong nucleus.J. Neurosci. 1992; 12: 2464-2477Crossref PubMed Google Scholar, 20Isaac J.T.R Nicoll R.A Malenka R.C Evidence for silent synapses implications for the expression of LTP.Neuron. 1995; 15: 427-434Abstract Full Text PDF PubMed Scopus (964) Google Scholar, 28Liao D Hessler N.A Malinow R Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice.Nature. 1995; 375: 400-404Crossref PubMed Scopus (1077) Google Scholar). During early development, several distinct changes in the properties of glutamatergic synaptic currents have been proposed to occur that alter this ratio of AMPA to NMDA receptor currents. Here, we discuss the functional implications of two of these changes. The first developmental change, which is supported by a large body of evidence, is that the amount of current passed by NMDA receptors is initially much greater than in adults and then declines rapidly with age and synaptic activity. This phenomenon was first observed in layers IV–VI of the kitten's primary visual cortex in vivo, where visual responses are initially highly sensitive to blockade by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP5), and this sensitivity declines abruptly with visual experience during the first weeks of life (36Tsumoto T Kagihara K Sato H Hata Y NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats.Nature. 1987; 327: 513-514Crossref PubMed Scopus (286) Google Scholar, 17Fox K Sato H Daw N The location and function of NMDA receptors in cat and kitten visual cortex.J. Neurosci. 1989; 9: 2443-2454Crossref PubMed Google Scholar, 18Fox K Daw N Sato H Czepita D The effect of visual experience on development of NMDA receptor synaptic transmission in kitten visual cortex.J. Neurosci. 1992; 12: 2672-2684Crossref PubMed Google Scholar). A basis for this effect was suggested by subsequent in vitro experiments, which showed that synaptic responses of layer IV neurons in rat visual cortical slices exhibit an NMDA receptor current whose duration declines severalfold over the first postnatal month (5Carmignoto G Vicini S Activity-dependent decrease in NMDA receptor responses during development of the visual cortex.Science. 1992; 258: 1007-1011Crossref PubMed Scopus (610) Google Scholar). Similar developmental decreases in NMDA receptor current duration have been observed during early development in other structures, including the lateral geniculate nucleus (35Ramoa A.S McCormick D.A Enhanced activation of NMDA receptor responses at the immature retinogeniculate synapse.J. Neurosci. 1994; 14: 2098-2105Crossref PubMed Google Scholar), the thalamocortical synapse in somatosensory barrel cortex (7Crair M.C Malenka R.C A critical period for long-term potentiation at thalamocortical synapses.Nature. 1995; 375: 325-328Crossref PubMed Scopus (598) Google Scholar), and the superior colliculus (19Hestrin S Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse.Nature. 1992; 357: 686-689Crossref PubMed Scopus (458) Google Scholar). The developmental reduction in NMDA receptor current duration must involve a modification of the NMDA receptor complex itself, since it is observed in excised membrane patches in response to glutamate application (19Hestrin S Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse.Nature. 1992; 357: 686-689Crossref PubMed Scopus (458) Google Scholar, 5Carmignoto G Vicini S Activity-dependent decrease in NMDA receptor responses during development of the visual cortex.Science. 1992; 258: 1007-1011Crossref PubMed Scopus (610) Google Scholar), and recent evidence suggests that it is likely to reflect a developmental switch in the subunit composition of the NMDA receptor (31Monyer H Burnashev N Laurie D.J Sakmann B Seeburg P.H Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.Neuron. 1994; 12: 529-540Abstract Full Text PDF PubMed Scopus (2877) Google Scholar, 14Flint A.C Maisch U.S Weishaupt J.H Kriegstein A.R Monyer H NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex.J. Neurosci. 1997; 17: 2469-2476Crossref PubMed Google Scholar). Thus, long-duration NMDA receptor currents give way to shorter-duration currents over the first few weeks of life, perhaps resulting from an activity-dependent switch in the subunit composition of the NMDA receptor. This progression would tend to cause a developmental reduction in the contribution of NMDA receptor currents to synaptic responses in vivo. A second change that has been proposed to occur during the maturation of glutamatergic synapses is more controversial, and involves an increase in AMPA receptor currents. A growing body of evidence suggests that early in development, many glutamatergic synapses express only NMDA receptor currents and lack AMPA currents entirely. Because the NMDA receptor passes current only at relatively depolarized postsynaptic membrane potentials due to a voltage-dependent blockade by magnesium ions (34Nowak L Bregestovski P Ascher P Herbet A Prochiantz A Magnesium gates glutamate-activated channels in mouse central neurons.Nature. 1984; 307: 462-465Crossref PubMed Scopus (3099) Google Scholar), these synapses generate little or no current when the postsynaptic cell is at a relatively hyperpolarized resting potential and thus have been termed "silent" synapses. Silent synapses can be revealed experimentally by depolarizing the postsynaptic cell above the threshold for NMDA receptor activation and observing an NMDA receptor current unaccompanied by an AMPA current. Synapses of this type are prevalent at early stages of development in several brain regions, including the optic tectum of Xenopus laevis (38Wu G.-Y Malinow R Cline H.T Maturation of a central glutamatergic synapse.Science. 1996; 274: 972-975Crossref PubMed Scopus (456) Google Scholar), the rat's barrel cortex (21Isaac J.T.R Crair M.C Nicoll R.A Malenka R.C Silent synapses during development of thalamocortical inputs.Neuron. 1997; 18: 269-280Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar), and the CA1 region of the rat's hippocampus (20Isaac J.T.R Nicoll R.A Malenka R.C Evidence for silent synapses implications for the expression of LTP.Neuron. 1995; 15: 427-434Abstract Full Text PDF PubMed Scopus (964) Google Scholar, 28Liao D Hessler N.A Malinow R Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice.Nature. 1995; 375: 400-404Crossref PubMed Scopus (1077) Google Scholar, 9Durand G.M Kovalchuk Y Konnerth A Long-term potentiation and functional synapse induction in developing hippocampus.Nature. 1996; 381: 71-75Crossref PubMed Scopus (668) Google Scholar). In these systems, AMPA receptor currents begin to appear and increase in amplitude over the same time period as the changes in NMDA receptor currents described above. The appearance of AMPA receptor currents causes a rapid decrease in the number of silent synapses and a shift from synapses with purely NMDA receptor pharmacology to synapses with the mature combination of both AMPA and NMDA receptor currents. The evidence supporting the existence of silent synapses in early development, though compelling, is not conclusive. An alternative explanation is that purely NMDAergic synapses do not exist, and instead, isolated NMDA receptor currents are observed when released glutamate diffuses to the synapse of interest from neighboring synapses on different postsynaptic cells. Such "spillover" of glutamate could selectively activate NMDA receptors, even if AMPA receptors coexist at the same synapse, because NMDA receptors have a higher affinity for glutamate than AMPA receptors, and the concentration of spilled-over glutamate would be relatively low (27Kullmann D.M Asztely F Extrasynaptic glutamate spillover in the hippocampus evidence and implications.Trends Neurosci. 1998; 21: 8-14Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar). In this view, the developmental reduction in the number of silent synapses would reflect a reduction in the amount of spillover occuring with age. Although this issue has yet to be settled, a role for silent synapses as the starting point in the maturation of glutamatergic synapses remains quite attractive. This is in part because LTP of silent synapses causes the rapid appearance of AMPA receptor–mediated currents (20Isaac J.T.R Nicoll R.A Malenka R.C Evidence for silent synapses implications for the expression of LTP.Neuron. 1995; 15: 427-434Abstract Full Text PDF PubMed Scopus (964) Google Scholar, 21Isaac J.T.R Crair M.C Nicoll R.A Malenka R.C Silent synapses during development of thalamocortical inputs.Neuron. 1997; 18: 269-280Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar, 28Liao D Hessler N.A Malinow R Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice.Nature. 1995; 375: 400-404Crossref PubMed Scopus (1077) Google Scholar, 9Durand G.M Kovalchuk Y Konnerth A Long-term potentiation and functional synapse induction in developing hippocampus.Nature. 1996; 381: 71-75Crossref PubMed Scopus (668) Google Scholar), suggesting that ongoing LTP may occur during early development to cause the steady accumulation of AMPA receptor currents at young synapses. Because LTP is generally thought to be input specific, this mechanism would allow individual synapses that drive the postsynaptic cell appropriately to be made functional, while inappropriately targeted synapses would remain nonfunctional and therefore would not interfere with circuit function (6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar). An important test of this hypothesis that needs to be examined is whether treatments that prevent LTP induction result in the abnormal preservation of silent synapses during early development. It should be noted that both of these phenomena, the change in the time course of NMDA receptor currents and the addition of AMPA receptor currents, make the proportion of synaptic current mediated by the NMDA receptor initially high and then decline with use. Thus, both phenomena may contribute to the changing relative contribution of AMPA and NMDA receptor currents to sensory responses in vivo. Indeed, for the thalamocortical synapse in rat barrel cortex and the retinotectal synapse in Xenopus, two systems in which both mechanisms have been examined, changes in both the proportion of silent synapses (38Wu G.-Y Malinow R Cline H.T Maturation of a central glutamatergic synapse.Science. 1996; 274: 972-975Crossref PubMed Scopus (456) Google Scholar, 21Isaac J.T.R Crair M.C Nicoll R.A Malenka R.C Silent synapses during development of thalamocortical inputs.Neuron. 1997; 18: 269-280Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar) and the duration of NMDA receptor currents (7Crair M.C Malenka R.C A critical period for long-term potentiation at thalamocortical synapses.Nature. 1995; 375: 325-328Crossref PubMed Scopus (598) Google Scholar, 6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar) occur during the same early developmental period. These early maturational changes in glutamatergic synaptic physiology have been studied carefully at the retinotectal synapse in Xenopus. In Xenopus tadpoles, neurogenesis occurs in a restricted region at the caudal edge of the developing optic tectum, so that immature neurons are found in the caudal tectum and progressively more mature neurons are found further rostrally (38Wu G.-Y Malinow R Cline H.T Maturation of a central glutamatergic synapse.Science. 1996; 274: 972-975Crossref PubMed Scopus (456) Google Scholar). This rostrocaudal developmental gradient allows glutamatergic synaptic maturation to be studied by recording from tectal neurons at different rostrocaudal locations in a single animal. Using whole-cell voltage-clamp recording techniques38Wu G.-Y Malinow R Cline H.T Maturation of a central glutamatergic synapse.Science. 1996; 274: 972-975Crossref PubMed Scopus (456) Google Scholar found that neurons in the caudal tectum, which were recently formed and morphologically immature, exhibited robust NMDA receptor currents but very low levels of AMPA receptor currents, with some neurons exhibiting no detectable AMPA receptor currents at all. In contrast, more mature neurons in the rostral tectum showed prominent AMPA receptor currents. Furthermore, by comparing synaptic failure rates at hyperpolarized and depolarized potentials, it is possible to estimate the fraction of synapses on each neuron that exhibit currents mediated solely by NMDA receptors. A strong correlation was observed between position along the rostrocaudal axis and the fraction of synapses exhibiting purely NMDAergic synaptic currents (38Wu G.-Y Malinow R Cline H.T Maturation of a central glutamatergic synapse.Science. 1996; 274: 972-975Crossref PubMed Scopus (456) Google Scholar). Because the synapses onto immature cells in the caudal tectum are newly formed, these results support the hypothesis that many or all glutamatergic synapses are formed as purely NMDAergic, silent synapses, and that these synapses are then converted to synapses with both AMPA and NMDA receptor components. In this view, the small proportion of silent synapses that persists in the rostral, mature tectum may reflect the continuing formation of retinotectal synapses, which occurs throughout larval life (6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar). In addition, immature tectal neurons were found to have NMDA receptor currents with durations twice as long as those of mature neurons, confirming that changes in NMDA receptor kinetics also occur during this early developmental period (Cline et al., 1997). Though these experiments demonstrate elegantly the maturational changes occurring at glutamatergic synapses during early development, they do not address the important functional question of whether these changes are use dependent and can therefore be regulated independently for each synapse, which would provide a powerful mechanism for adjusting the functional properties of developing networks (6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar), or whether instead these changes reflect the developmental stage of the postsynaptic neuron and therefore occur in parallel for all synapses onto a given tectal cell. The capacity for different synapses to mature independently has been suggested by experiments in the inferior colliculus of the barn owl (Tyto alba), where altered experience during late stages of development can cause the appearance of novel auditory responses mediated by newly functional synaptic inputs. Neurons in the owl's external nucleus of the inferior colliculus (ICX) are tightly tuned for binaural sound localization cues, including interaural time difference (ITD), the microsecond difference in arrival time of a sound at each of the owl's ears. ICX neurons are arranged into a map of ITD and receive input via a topographic projection from the central nucleus of the inferior colliculus (ICC), which contains a similar ITD map (25Konishi, M., Takahashi, T., Wagner, H., Sullivan, W.E., and Carr, C.E. (1988). Neurophysiological and anatomical substrates of sound localization in the owl. In Auditory Function, G.M. Edelman, W.E. Gall, and W.M. Cowan, eds. (Wiley and Sons: New York, pp. 721–746).Google Scholar). The tuning of ICX neurons for ITD and other sound localization cues is calibrated by vision during a sensitive period that ends late in development, at the age of sexual maturity (3Brainard M.S Knudsen E.I Experience-dependent plasticity in the inferior colliculus a site for visual calibration of the neural representation of auditory space in the barn owl.J. Neurosci. 1993; 13: 4589-4608PubMed Google Scholar, 4Brainard M.S Knudsen E.I Sensitive periods for visual calibration of the auditory space map in the barn owl optic tectum.J. Neurosci. 1998; 18: 3929-3942Crossref PubMed Google Scholar). During the sensitive period, existing circuits can be substantially modified by altered visual experience. For example, when owls are subjected to a sustained horizontal displacement of the visual field by wearing prismatic spectacles, ICX neurons acquire novel auditory responses, termed "learned responses," to values of ITD outside of their normal tuning range (3Brainard M.S Knudsen E.I Experience-dependent plasticity in the inferior colliculus a site for visual calibration of the neural representation of auditory space in the barn owl.J. Neurosci. 1993; 13: 4589-4608PubMed Google Scholar, 11Feldman D.E Knudsen E.I An anatomical basis for visual calibration of the auditory space map in the barn owl's midbrain.J. Neurosci. 1997; 17: 6820-6837PubMed Google Scholar). During the first few weeks of prism experience, many neurons simultaneously express both learned responses and responses to their normal ITD range ("normal responses") that had been expressed before prism attachment. This results in broad ITD tuning curves containing both types of responses. With additional prism experience, normal responses are eliminated and ITD tuning curves become centered on the learned response. The acquisition of learned responses reflects synaptic modification occurring in the ICX (3Brainard M.S Knudsen E.I Experience-dependent plasticity in the inferior colliculus a site for visual calibration of the neural representation of auditory space in the barn owl.J. Neurosci. 1993; 13: 4589-4608PubMed Google Scholar) and appears to involve a systematic anatomical change in the topography of the ICC–ICX projection, such that ICX neurons acquire abnormal inputs from locations in the ICC that encode the learned range of ITDs (11Feldman D.E Knudsen E.I An anatomical basis for visual calibration of the auditory space map in the barn owl's midbrain.J. Neurosci. 1997; 17: 6820-6837PubMed Google Scholar). This finding strongly suggests that new synaptic connections develop to mediate learned responses. By comparing the pharmacology of learned responses, which are presumably mediated by circuits incorporating recently formed synapses, with that of normal responses, which are thought to be mediated by the preexisting ICX circuitry, it is possible to ask the question: is the development of glutamatergic synaptic transmission recapitulated when novel synaptic connections form as a consequence of experience-dependent plasticity late in development? In vivo iontophoresis of glutamate receptor antagonists has shown that excitatory synaptic transmission of auditory responses in the ICX is mediated by both NMDA and non-NMDA, presumably AMPA, receptors (10Feldman D.E Knudsen E.I NMDA and non-NMDA glutamate receptors in auditory transmission in the barn owl inferior colliculus.J. Neurosci. 1994; 14: 5939-5958Crossref PubMed Google Scholar). In owls raised with normal vision, the proportion of auditory-evoked action potentials blocked by AP5 is constant across the entire range of ITDs to which a neuron responds, indicating that the relative contribution of NMDA and AMPA receptor currents to ICX responses (the NMDA/AMPA current ratio) is uniform across the synapses mediating these responses (12Feldman D.E Knudsen E.I Pharmacological specialization of learned auditory responses in the inferior colliculus of the barn owl.J. Neurosci. 1998; 18: 3073-3087Crossref PubMed Google Scholar). In contrast, in owls in which learned responses have been recently induced by prism experience, learned responses are much more sensitive to NMDA receptor antagonists than are normal responses expressed by the same ICX neurons (13Feldman D.E Brainard M.S Knudsen E.I Newly learned auditory responses mediated by NMDA receptors in the owl inferior colliculus.Science. 1996; 271: 525-528Crossref PubMed Scopus (74) Google Scholar, 12Feldman D.E Knudsen E.I Pharmacological specialization of learned auditory responses in the inferior colliculus of the barn owl.J. Neurosci. 1998; 18: 3073-3087Crossref PubMed Google Scholar). Both responses are equally sensitive to broad-spectrum glutamate receptor antagonists, however, indicating that synapses mediating learned responses have a higher NMDA/AMPA current ratio than synapses mediating normal responses. This increased NMDA/AMPA current ratio persists from the time learned responses first appear at about 80 days of age until the owls mature, at just over 200 days of age, when the NMDA/AMPA current ratio of learned responses declines to the same ratio exhibited by normal responses (12Feldman D.E Knudsen E.I Pharmacological specialization of learned auditory responses in the inferior colliculus of the barn owl.J. Neurosci. 1998; 18: 3073-3087Crossref PubMed Google Scholar). Learned auditory responses in these juvenile owls therefore display a pharmacological profile that is similar to maturing glutamatergic synapses during early development: they initially exhibit a high NMDA/AMPA current ratio, and after an extended period this ratio declines to the value observed in the adult. Whether the high initial NMDA/AMPA ratio reflects an initial enhancement of NMDA receptor currents at synapses mediating learned responses, an initial paucity of AMPA receptor currents, or some other cause, is unknown. One possibility is that the synapses mediating learned responses form during prism experience as synapses with long-duration NMDA receptor currents, and that the duration of these currents then falls with age or synaptic activity. Another possibility is that synapses form during prism experience as silent synapses, and that learned responses develop when a subset of these silent synapses are reinforced by an LTP-like process, causing the appearance of enough AMPA receptor current to elicit a reliable postsynaptic response. Learned responses mediated by such synapses would be expected to have an NMDA/AMPA current ratio that is higher than that of the older, more mature synapses mediating normal responses on the same ICX neurons. With additional prism experience, more reinforcement could gradually occur, increasing the AMPA receptor component at these synapses until the NMDA/AMPA ratio falls to within the normal range. It should be noted that in both of these models, learning involves the formation of new synapses (either in a directed or a nondirected manner) and not simply the adjustment of the efficacy of existing synapses. The attainment of normal pharmacology could also be triggered by an extrinsic maturational signal related to the end of the juvenile period of enhanced plasticity, which closes at about the same age as when the NMDA/AMPA current ratio reaches the normal ratio (4Brainard M.S Knudsen E.I Sensitive periods for visual calibration of the auditory space map in the barn owl optic tectum.J. Neurosci. 1998; 18: 3929-3942Crossref PubMed Google Scholar). Because this age is also coincident with sexual maturation, one candidate signal is the level of sex hormones, which increases when birds become sexually mature (30Marler P Peters S Wingfield J Correlations between song acquisition, song production, and plasma levels of testosterone and estradiol in sparrows.J. Neurobiol. 1987; 18: 531-548Crossref PubMed Scopus (77) Google Scholar). Song learning in zebra finches is known to be regulated in this manner: low levels of steroid hormones are permissive for song learning when animals are juveniles, and when levels increase, either during normal sexual maturation or through experimental manipulation, song learning is arrested (2Bottjer S Neural and hormonal substrates for song learning in zebra finches.Semin. Neurosci. 1991; 3: 481-488Crossref Scopus (13) Google Scholar). The findings discussed above have implications for synaptic transmission in structures that retain the capacity for synaptogenesis in the juvenile period and even into adulthood. Where synapse formation is ongoing, as in the optic tectum of larval Xenopus (6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar) and in the hippocampus of adult rats (37Woolley C.S McEwen B.S Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat.J. Neurosci. 1992; 12: 2549-2554Crossref PubMed Google Scholar), the relative contributions of NMDA and AMPA receptors to normal synaptic transmission may reflect not only an intrinsic, age-dependent NMDA/AMPA ratio associated with synapses in that region, as is traditionally thought, but may also depend critically on the rate of ongoing synaptogenesis. Where synapse formation is induced by altered experience or loss of peripheral input (e.g.,8Darian-Smith C Gilbert C.D Axonal sprouting accompanies functional reorganization in adult cat striate cortex.Nature. 1994; 368: 737-740Crossref PubMed Scopus (520) Google Scholar, 15Florence S.L Kaas J.H Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys.J. Neurosci. 1995; 15: 8083-8095Crossref PubMed Google Scholar), the NMDA/AMPA current ratio would be predicted to vary with the amount of synaptic reorganization that is occurring. This possibility suggests an intriguing hypothesis for why learned responses in the barn owl exhibit a high NMDA/AMPA current ratio for so long and return to an apparently normal ratio at an age corresponding to the end of the sensitive period of enhanced plasticity. One interpretation for the modification of ICC–ICX synaptic connectivity during the sensitive period is that ongoing synaptogenesis occurs in the ICX throughout this period, with new synapses that mediate learned responses being selectively retained. Because newly formed synapses have a relatively high NMDA/AMPA receptor current ratio, continual addition of newly formed synapses to mediate learned responses might keep the NMDA receptor–mediated proportion of these responses high as long as new synapses continue to be created. Only when synaptogenesis slows or comes to a halt, as might occur with the close of the juvenile period, would maturation of the existing synapses reduce the NMDA/AMPA current ratio of learned responses to the ratio observed for normal responses. Together, these observations suggest the following general hypothesis: during early development, neural networks are established by genetically specified cues and activity-dependent processes. Glutamatergic synapses that form during this period display a rapid, activity-dependent maturation of NMDA and AMPA receptor currents, so that by the time basic networks have been established, glutamatergic pharmacology is much like that observed in the adult. Subsequently, there occurs an extended, late period of development during which established networks are modified by experience, in part through the formation and selective stabilization of novel glutamatergic synapses. These novel synapses are created initially as either synapses with long-duration NMDA receptor currents and/or as silent, purely NMDAergic synapses, recapitulating the maturation of glutamatergic synaptic currents in early development. In either case, the high NMDA/AMPA current ratio of such synapses would be beneficial in enabling rapid activity-dependent adjustment of synaptic strength by NMDA receptor-dependent mechanisms (22Katz L.C Shatz C.J Synaptic activity and the construction of cortical circuits.Science. 1996; 274: 1133-1138Crossref PubMed Scopus (2372) Google Scholar). If novel synapses were formed as silent synapses, an additional advantage would be gained: because synapses would be made functional only if they were appropriately targeted, the presence of inappropriate synapses would not adversely affect the performance of the preexisting circuit (6Cline H.T Wu G.-Y Malinow R In vivo development of neuronal structure and function.Cold Spring Harbor Symp. Quant. Biol. 1996; 61: 95-104Crossref PubMed Google Scholar). Thus, large-scale adaptive adjustments could be made, for example, by nondirected axonal outgrowth and synapse formation, followed by the selective activation of appropriate synapses. In this model, network optimization could proceed without jeopardizing normal function, an essential feature if plasticity is to occur in a circuit that is necessary for the survival of the animal. This is certainly the case for the barn owl, in which ICX plasticity takes place at an age when juvenile owls have left the nest and depend on sound localization to find their prey. Finally, by the end of the late developmental period, which coincides with sexual maturation, the capacity for synaptogenesis is dramatically restricted, reducing the ability of many networks to adapt to novel changes in sensory or motor experience. Within the juvenile period, this restriction may occur earlier for low order networks and at progressively later ages for high order networks (16Fox K Zahs K Critical period control in sensory cortex.Curr. Opin. Neurobiol. 1994; 4: 112-119Crossref PubMed Scopus (59) Google Scholar). A prediction of this model is that, except for brain regions in which the capacity for synaptogenesis persists throughout life, experience-dependent changes in neural circuits in the adult will be mediated primarily through changes in the efficacy of the synapses that exist at the end of the juvenile period. Thus, experience during the juvenile period may be critical in establishing the repertoire of connectional states available to the adult nervous system (23Knudsen E.I Capacity for plasticity in the adult owl auditory system expanded by juvenile experience.Science. 1998; 279: 1531-1533Crossref PubMed Scopus (131) Google Scholar).