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Rules of engagement: factors that regulate activity-dependent synaptic plasticity during neural network development.


The life cycle of vast numbers of plants and animals involves an early period of massive cell proliferation followed by a competition-based organism death, which maximizes health of that generation and results in a stable population of organisms. Obvious examples include blooms of phytoplankton and egg laying by sea turtles. This ubiquitous process of overproduction and pruning can also be observed in cell number during embryonic, fetal, and neonatal development of many tissue systems. Similar to organism development, tissue development usually involves a competition between cells for space and resources. This idea has been applied in interesting ways to nervous systems (Turkewitz and Kenny, 1985; Edelman, 1993). Through activity-based refinement processes that regulate programmed cell death, cell number is trimmed during the final maturation phase (Hutchins and Barger, 1998). The influence of activity on cell survival or death during development is mediated in large part through synaptic transmission (Table 1). Studying the ways that synapses change during development can thus be a fruitful means to better understand the complex regulation of nervous tissue maturation (Miller, 1994).
Table 1
General life cycle of post-mitotic neurons

 Period            Process                   Regulators

Prenatal   Proliferation          Mitosis

           Differentiation        Genetics/epigenetics

           Migration              Actin filaments/integrins

Postnatal  Synaptogenesis         Filopodia/cell adhesion/receptor

           Synapse pruning        Synaptic depression

           Neuron death           Apoptosis

           Synapse stabilization  Synaptic potentiation

           Neuron survival        Trophic factors

The overproduction and pruning process also applies to synapses in developing networks. One dramatic example occurs in layer 4 of the visual cortex in what are called ocular dominance columns (Crowley and Katz, 2002). In any one column in the adult animal, incoming axons are connected (indirectly) to only one eye, while axons in the neighboring column originate from the other eye. However, prior to eyelid parting, there is little bias and inputs arrive in any given column from either eye. Shown first in the newborn cat, specificity of input to ocular columns is achieved by an activity-dependent elimination of many of the original terminal connections from one or the other eye (Wiesel and Hubel, 1965). Likewise, in the case of motor systems, in early development, many different motor neurons synapse onto the same muscle fiber. In addition, many muscle fibers are innervated by the same axon. With patterned input during maturation, each muscle fiber becomes innervated by one and only one motor neuron (Sanes and Lichtman, 1999).

Cognitive systems are no exception to the overproduction rule. In the rodent hippocampus, synapses are produced by the thousands each minute during early postnatal development (Harris et al., 1992). Production declines and pruning persists during the third postnatal week, resulting in a net loss of synapses (Bagri et al., 2003; Liu et al., 2005). Similarly, in the human neocortex, synapse density peaks at around 2 years of age, after which synapses are lost faster than they are produced, resulting in a 60% decline by adolescence (Huttenlocher et al., 1982). It is thought that the initial synaptic overproduction is relatively independent of the animal's experiences, but that experience-based activity is a determining factor in which synapses will be selectively retained or eliminated (Greenough et al., 1987; Eisenberg, 1999; Bastrikova et al., 2008). The phenomenon is clear and clearly important in generating neural systems that are efficient and specified in function. What are unclear are the physiological mechanisms at synapses that subserve this essential shaping process within nervous systems. As a bonus, knowing how a brain organizes itself as it is being built can be a profitable means to understand how brain function is organized in adulthood.

Glutamate Synapses: The Primary Model

In the adult brain, glutamate serves predominantly to allow neurons to excite each other. Glutamate released from presynaptic terminals binds to postsynaptic receptors, resulting in a fast depolarization that, when large enough, leads to postsynaptic action potential (AP) discharge (Dingledine et al., 1999). Adult glutamate synapses express activity-dependent functional and structural changes that impact network dynamics in creatures ranging from hydra (Kay and Kass-Simon, 2009), to nematodes (Kano et al., 2008), to humans (Wankerl et al., 2010). Most types of learning and memory involve plasticity at glutamatergic synapses. Even when there is no explicit goal, synaptic function is altered upon exposure to novel, enriched, and impoverished environments (Gagne et al., 1998; Foster and Dumas, 2001; Nithianantharajah and Hannan, 2006). Moreover, glutamatergic synapses are modified during hibernation (von der Ohe et al., 2006, 2007) and during recovery from brain injury (Duffau, 2006), and they tune themselves to changes in input during postnatal development (Waites et al., 2005). This review focuses on the latter--physiological alterations during development--as a means to better understand the factors that govern maturation of neural networks (Table 1). One major focus is developmental modification of the threshold for the induction of synaptic plasticity, as this is the turning point at which a synapse is either potentiated and stabilized or depressed and eliminated. The total sum of synaptic decisions to stabilize or deteriorate impacts the overall decision of the neuron to live or die. For instance, cortical gray matter loss continues through age 20 in humans (Gogtay et al., 2004) in parallel with synapse loss. This not only shapes networks during maturation but also has implications for the health and function of nervous tissues across the lifespan.

Attention has focused on late postnatal development of synapses in forebrain structures of rats and mice (beginning roughly 2 weeks after birth), mostly in relation to the maturation of perceptual and cognitive abilities. At glutamatergic synapses in the visual cortex and hippocampus, dramatic changes in activity-dependent synaptic plasticity occur after the end of the second postnatal week, including modifications in the magnitude of expression and the requirements for induction. Here, we first define experimental models of activity-dependent synaptic plasticity in the rat and mouse visual cortex and hippocampus in order to introduce the general reader to contemporary methods for data collection and analysis. A table of important terms is included for clarity (Table 2). Next, we review findings documenting developmental alterations in experimentally induced long-lasting synaptic plasticity, including the shift in the threshold for plasticity induction. We then describe one prevailing model put forth in an attempt to explain the observed changes in synaptic plasticity across late postnatal development, which is centered on an alteration in the subunits that compose the glutamate-sensitive N-methyl-D-aspartate (NMDA) receptor, a central player in activity-dependent synaptic plasticity across species. At this point, many other factors that likely influence developmental alterations in synaptic plasticity are discussed, highlighting synaptic processes upstream and downstream from NMDA receptor activation. The paper concludes with a broader perspective on how alterations in physiological plasticity relate to network maturation.
Table 2
Key terms

Full termAdenylate cyclase     Abbreviation AC  Definition Enzyme that
                                                converts ATP to cAMP

[alpha]-Amino-3-hydroxyl-5-    AMPA receptor    Fast ionotropic
methyl-4-isoxazole-propionate                   glutamate receptor,
receptor                                        main source of

Action potential               AP               All-or-nothing
                                                electrical discharge
                                                of a neuron

Excitatory postsynaptic        EPSP             Voltage generated by
potential                                       excitatory synaptic

Excitatory postsynaptic        EPSC             Current generated by
current                                         excitatory synaptic

Calmodulin                     CaM              Calcium binding
                                                protein, translates
                                                calcium signal to

Calmodulin-dependent kinase    CaMKII           Autophosphorylating
II                                              enzyme that is
                                                required for LTP
                                                induction in adults

Cooperativity                                   Spatial summation of
                                                synaptic responses
                                                necessary for LTP

Cyclic adenosine               cAMP             Signaling molecule
monophosphate                                   that activates PKA

Glutamate                                       Excitatory

Gamma-aminobutyric acid        GABA             Inhibitory

Inhibitory protein 1           I-1              Negative regulator of

Long-term potentiation         LTP              Activity-dependent
                                                long-lasting increase
                                                in synaptic efficacy

Long-term depression           LTD              Activity-dependent
                                                long-lasting decrease
                                                in synaptic efficacy

N-methyl-D-aspartate receptor  NMDA receptor    Ionotropic glutamate
                                                receptor that conducts

Paired-pulse facilitation      PPF              Short-term increase in
                                                reflecting low
                                                baseline transmitter
                                                release probability

Plasticity induction           [theta]          Border at which
threshold                                       induction shifts from
                                                producing LTD to LTP,
                                                or the lowest
                                                induction frequency
                                                that produces LTP

Protein kinase A               PKA              Cyclic AMP-dependent
                                                protein kinase that is
                                                required for LTP in

Protein phosphatase 2B         calcineurin      Phosphatase involved
                                                in LTD

Protein phosphatase 1          PP1              Phosphatase required
                                                for LTD

Schaffer collateral synapse    SC-CA1           Junction between CA3
                                                and CA1 pyramidal
                                                cells in the

Lessons From Living Brain Slices

A vast majority of experiments on synaptic plasticity employ living forebrain slice preparations and electrical stimulation. Cortical and hippocampal slices are robust under in vitro conditions for many hours after preparation (a recovery incubation period of 1 to 2 h normally follows slice preparation), allowing for precise electrode placement and enabling experiments that are inherently long (lasting many hours). Also, recording in slices allows for greater control of activity and, hence, factors that regulate plasticity. Typically, fine-metal stimulating electrodes and glass recording microelectrodes are used, respectively, to stimulate afferents and record from activated synaptic populations. A tiny electrical discharge from the stimulating electrode activates adjacent axons, producing APs. These APs propagate to synapses and elicit excitatory postsynaptic potentials (EPSPs). In this configuration, it is possible to stimulate a homogenous group of afferent axons and record relatively pure excitatory glutamatergic synaptic responses, especially in laminated structures. One example is stimulation of lateral geniculate axons ascending from the visual portion of the thalamus and recording of synaptic responses elicited in layer 4 pyramidal neurons in the visual cortex (Fig. 1A). Layer 4 to layer 2/3 synapses in primary visual cortex are frequently examined in the same manner because this synaptic contact is thought to be the initial site for ocular dominance plasticity (Trachtenberg et al., 2000). In a majority of hippocampal slice experiments, CA3 pyramidal cell axons (Schaffer collaterals) are activated, and evoked synaptic responses are recorded in area CA1 (SC-CA1 synapses, Fig. 1B). By moving the electrodes, perforant path and mossy fiber synaptic responses in other hippocampal areas can be recorded in the same preparation under the same conditions. To assess the primary excitatory synaptic response, the initial descending phase of the extracellular EPSP is usually analyzed (diagonal arrows in Fig. 2A and 2B insets point to the descending EPSP slope). This is because, at later time points, the waveform becomes contaminated by other factors such as postsynaptic discharge and di-synaptic events.



Long-term plasticity experiments normally start with a baseline recording period of at least 15 min to demonstrate stability in the population synaptic response (Fig. 2). By convention, single pulses are delivered every 30 s because this stimulation rate does not itself induce changes in synaptic function and the sampling rate is sufficient. Once a stable baseline is established, the stimulation frequency is briefly altered to induce plasticity, and then recording resumes at the same stimulating frequency used during the baseline period. Plasticity-induction protocols generally entail trains of stimulus pulses at frequencies ranging from 1 pulse every 2 s to 200 pulses per s that are applied to a population of afferents simultaneously. It is important to note that these stimulus patterns also elicit short-term plasticity during the induction phase (lasting into the post-induction recording period), which should be considered when attempting to determine the factors that influence the threshold for plasticity induction.

Long-term potentiation (LTP) and long-term depression (LTD) refer to lasting increases and decreases in synaptic efficacy that are produced by selective patterns of input activity. There is abundant evidence that these experimental forms of synaptic plasticity are suitable models for the types of changes synapses undergo with natural activity (Gruart and Delgado-Garcia, 2007; Frey and Frey, 2008). At most glutamate synapses, LTP or LTD induction involves activation of NMDA receptors. NMDA receptors are special because they not only require glutamate binding to change receptor conformation but also necessitate postsynaptic depolarization to remove a magnesium blockade at the ion pore (Nowak et al., 1984; Mayer and Westbrook, 1987), allowing them to detect coincident pre-and postsynaptic activity. Under standard recording conditions, LTP is triggered by brief (subseconds to seconds) stimulation epochs of about 10-200 Hz (Fig. 2A), while LTD requires induction periods in the range of seconds to minutes with frequencies ranging from 0.5 to 5 Hz (Malenka and Bear, 2004) (Fig. 2B). However, the border at which induction frequency shifts from producing LTD to LTP (plasticity induction threshold, [theta]) varies according to the developmental state of the animal (Bienenstock et al., 1982; Mayford et al., 1995).

The importance of multiple synaptic activations for plasticity induction is apparently that they provide adequate postsynaptic depolarization to sufficiently activate NMDA receptors. Temporal summation produced by high-frequency stimulation of individual synapses (Douglas and Goddard, 1975), spatial summation produced by coactivation of different synapses on the same postsynaptic cell (cooperativity, McNaughton, 1982), and APs back-propagating into dendrites from the cell body can all supply enough depolarization to activate NMDA receptors (Magee and Johnston, 1997; Markram et al., 1997). Additionally, LTP can be induced at lower frequencies if the postsynaptic membrane is experimentally depolarized (Kelso and Brown, 1986; Wigstrom and Gustafsson, 1986; Meredith et al., 2003) or if the amount of magnesium in the perfusion solution is reduced (Dumas, 2010). Both LTP and LTD require calcium entry into the postsynaptic spine, typically through NMDA receptors (Fig. 3). Acting primarily through the calcium-binding protein calmodulin (CaM), the intracellular rises in calcium activate kinases or phosphatases that differentially regulate synaptic strength (Lisman et al., 2002). The direction of change in synaptic strength following higher or lower stimulation frequencies appears related to the amount of calcium that enters the postsynaptic spine during induction (Teyler et al., 1994; Ismailov et al., 2004) and to differential activation of postsynaptic kinases and phosphatases (Colbran, 2004).


Both LTP and LTD are expressed, in part, through modifications in the number and function of the glutamatesensitive fast ionotropic [alpha]-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors (Malenka and Bear, 2004), which alter the postsynaptic responsiveness to presynaptic glutamate release. LTP also involves a delayed and lasting increase in glutamate release (Zakharenko et al., 2001, 2003) and synapse growth (Matsuzaki, 2007; De Roo et al., 2008). In a circular fashion, the number of AMPA receptors at baseline and the dynamics of transmitter release during induction likely influence the degree of NMDA receptor activation by controlling the level of postsynaptic depolarization during synaptic activation. Therefore, the initial states of pre-and postsynaptic efficacy, both of which are altered during late postnatal development, regulate the process of plasticity induction. Likewise, basal states of molecular effectors downstream from NMDA receptor activation can influence the direction and magnitude of long-lasting synaptic plasticity. For instance, an increase in activation of calmodulin-dependent kinase II (CaMKII), considered a mediator of LTP, shifts the plasticity induction threshold toward LTD when the increase occurs prior to plasticity induction (Mayford et al., 1995). As such, in addition to developmental changes in NMDA receptors, age-related modifications in numerous other synaptic processes have the potential to regulate plasticity induction and expression as synapses mature.

Short summary

Living brain slices are useful physiological models primarily because they are easy to manipulate and are not impacted by ongoing brain activity during recording, allowing for more detailed mechanistic experiments. These brain slices exhibit activity-dependent synaptic plasticity. In vivo events occurring prior to slice preparation, like developmental stage and experience, produce enduring changes that carry over into the slice, making it possible to study how these factors affect synapse function. LTP and LTD are two popular experimental phenomena that are believed to be informative with regard to how activity regulates synaptic efficacy in an intact organism. The molecular and biophysical properties of LTP and LTD change during late postnatal development as neural networks are undergoing their final maturation. Likewise, other basic properties of synaptic function are altered. This reduced postnatal slice preparation presents a means to identify critical factors in the developmental regulation of synaptic plasticity, which will provide a better understanding of the rules that govern maturation of complex neuronal networks.

Developmental Alterations in Long-Term Potentiation and Long-Term Depression

By studying developmental changes in LTP and LTD, it is possible to learn about the sensitivity of developing networks in vivo to different patterns of activity. In the visual cortex, LTP and LTD are largest just before eyelid parting around postnatal day (P) 14, and the magnitude of both forms of plasticity then declines with age and visual activity (Fagiolini et al., 1994; Kirkwood et al., 1995; Crair and Malenka, 1995, Feldman and Knudsen, 1998; Yoshimura et al., 2003). Similarly, high-frequency stimulation of SC-CA1 afferents in hippocampal slices potentiates synaptic transmission to the greatest extent around the end of the second postnatal week, with reduced effects observed in adult tissue (Harris and Teyler, 1984, Teyler et al., 1989; Dudek and Bear, 1993; Durand et al., 1996). LTD induced by low-frequency stimulation is robust in the juvenile hippocampus and is difficult to induce after 3 weeks of age (Dudek and Bear, 1993; Overstreet et al., 1997; Nosyreva and Huber, 2005). Combined, the findings suggest that the threshold for plasticity induction at forebrain synapses changes during late postnatal development.

In the visual cortex, increased input resulting from eyelid parting at the end of the second postnatal week adjusts the ability to induce LTP and LTD (Kirkwood et al., 1996; Philpot et al., 2003). A sliding threshold model, first proposed by Beinenstock, Cooper, and Munro (Bienenstock et al., 1982) and summarized by Abraham (2008), provides an explanation for how prior activity can alter the ability to induce LTP or LTD in the visual cortex. On shorter time-scales, this model explains how network homeostasis may be achieved by changes in synaptic strength when overall activity is increased or decreased (Bear, 2003). On longer time scales--for instance, across late postnatal development, when synaptic numbers and weights are still being adjusted--this model is also appropriate. While developmental changes in input activity to the hippocampus are more difficult to define than in sensory systems, similar developmental alterations in the ability to induce LTP and LTD are present (Dudek and Bear, 1993), and maturation rate of hippocampal synapses is sensitive to changes in experience (Dumas, 2004).

Considering the NMDA receptor as a central point, the additional and enhanced forms of synaptic plasticity present at immature synapses are likely the result of upstream alterations in baseline synaptic strength (excitatory and inhibitory), in NMDA receptor function itself, and in expression and function of downstream protein kinase and phosphatase effector systems. Late postnatal changes in NMDA receptor function and synaptic plasticity are of great interest because they appear to signal a reduction in the malleability of developing neuronal networks and a transition from immature to mature perceptual and cognitive abilities (Roberts and Ramoa, 1999; Dumas, 2005a; Yashiro and Philpot, 2008), highlighting a need for a balance between plasticity and stability for optimal information processing and storage.

Short summary

The maintenance and removal of synapses during postnatal development involves LTP and LTD. Both LTP and LTD undergo changes in biophysical induction properties and molecular mechanisms of expression during late postnatal development of forebrain structures. Numerous models have been created to try to explain the developmental alterations in synaptic plasticity, including a sliding threshold model that considers the impact of prior activity. While a sliding threshold model may be appropriate to describe how developmental changes in input activity modify the induction and expression of synaptic plasticity, the physiological and molecular mechanisms that guide the plasticity shift are not well understood.

Developmental Regulation of the Threshold for Plasticity Induction: NMDA Receptor Composition

Developmental alterations in LTP and LTD induction in the forebrain occur at an age when the composition of synaptic NMDA receptors changes (Dumas, 2005b) (Fig. 3). NMDA receptors are mostly quatramers containing two obligatory NR1 subunits and two auxiliary NR2 subunits (although as many as 1/3 of the total NMDA receptors may consist of NR1, NR2A, and NR2B subunits) (Monyer et al., 1992; Al-Hallaq et al., 2007). NMDA receptors with NR2A or NR2B subunits have distinct functional properties. One main difference is shape of the synaptic response, with NR2A-containing NMDA receptors having faster rising and decay kinetics than NR2B-containing NMDA receptors (Carmignoto and Vicini, 1992; Crair and Malenka, 1995; Kirkwood et al., 1995; Flint et al., 1997; Barria and Malinow, 2002; Lopez De Armentia and Sah, 2003), resulting from higher open probability and faster deactivation (Chen et al., 1999; Erreger et al., 2005). At low frequencies, NR2B-containing NMDA receptors may conduct more calcium due to slower inactivation (Sobczyk et al., 2005). It has been postulated that, at higher frequency activation, NR2A-containing NMDA receptors may conduct more calcium due to higher open probability (Erreger et al., 2005), although no activation threshold for greater calcium conduction by NR2A-containing NMDA receptors has been established. Additionally, the intracellular C-termini of NR2A and NR2B (which are much longer than all other glutamate receptor subunit C-termini) interact with different anchoring proteins and contain different signaling domains (Yashiro and Philpot, 2008). One or more of these NR2 subunit-dependent alterations in NMDA receptor function are likely to influence the ability to induce plasticity.

In the forebrain, synaptic NMDA receptors initially contain NR2B subunits but are replaced by NMDA receptors with NR2A subunits during late postnatal development (reviewed in Dumas, 2005b). This developmental switch appears to be due in part to changes in gene expression because NR2B mRNA and protein levels decrease slightly during the third postnatal week (Laurie et al., 1997; Takai et al., 2003) and NR2A mRNA and protein levels increase in parallel (Watanabe et al., 1994; Monyer et al., 1994; Sheng et al., 1994; Zhong et al., 1995; Portera-Cailliau et al., 1996). Post-translational palmitoylation at separate cysteine clusters of the NR2 C-terminus regulates trafficking to the cell surface and sequestering at the Golgi apparatus (Hayashi et al., 2009). In addition, developmental alterations in anchoring proteins in the postsynaptic density permit insertion of more NMDA receptors with NR2B subunits during the first two postnatal weeks and NMDA receptors with NR2A subunits with increasing age thereafter (Elias et al., 2008). Greater synaptic incorporation of NMDA receptors with NR2A subunits results in NMDA receptor currents that dissipate more quickly with increasing age (Carmignoto and Vicini, 1992; Quinlan et al., 1999; Barth and Malenka, 2001; Yoshimura et al., 2003; Bellone and Nicoll, 2007). Thus, one might guess that mature synapses containing a greater ratio of NR2A to NR2B subunits and having shorter duration synaptic responses would not display summation as readily. To this point, no difference in NMDA receptor response summation in cortical neurons has been noted between wildtype mice and transgenics that overexpress NR2B subunits at 10-40 Hz (Philpot et al., 2001). However, NR2B protein levels in cortex were not increased by transgenic NR2B overexpression. NR2A knockout mice display increased NMDA receptor response summation relative to wildtypes (Philpot et al., 2007) (Fig. 3). Consequently, an increase in the NR2A to NR2B ratio and a reduction in temporal summation could explain the reduction in LTP magnitude in the developing hippocampus across the third postnatal week and in the visual cortex following eyelid parting (Fig. 4). However, more recent findings suggest that the developmental reduction in LTP magnitude might also be explained by the change in the intracellular portion of the NR2 subunit, the C-terminus. By expressing chimeric and truncated NR2 subunits in organotypic hippocampal cultures, it was shown that LTP induction was influenced most strongly by the presence or absence of the NR2B C-terminus (Kohr et al., 2003; Foster et al., 2010). So, the debate over the specific NMDA receptor properties that regulate the direction and magnitude of lasting alterations in synaptic efficacy lingers.


Given the importance of NMDA receptors for plasticity induction and the concurrent changes in NMDA receptor composition and plasticity induction threshold with maturation, it is reasonable to suspect that the NR2 exchange regulates the direction and induction threshold for synaptic plasticity. One theory, elegantly proposed by Yashiro and Philpot (2008), suggests that the developmental shift in the NR2A/NR2B ratio underlies the sliding threshold for synaptic plasticity. More explicitly, they claim that as the NR2A/NR2B ratio increases with age, it produces an increase in the threshold to induce LTP (a necessity for higher induction frequencies) (Fig. 4A), and propose a tight association between CaMKII with NR2B as a major factor that enhances LTP induction at more immature synapses. This model does well in explaining developmental alterations in LTP in visual cortex, but is in conflict with the concomitant decrease in LTD with age in cortex and hippocampus. Also, hippocampal recordings in NR2A knockout mice reveal a rightward shift in the threshold to induce LTP (Fig. 4B), suggesting that the presence of NR2A reduces LTP induction threshold in the hippocampus (Kiyama et al., 1998). Moreover, LTP is more closely associated with cyclic AMP-dependent protein kinase (PKA), than with CaMKII activity when NR2B to NR2A ratio is high at 2 weeks of age (Wikstrom et al., 2003; Yasuda et al., 2003), and CaMKII expression increases when the NR2B to NR2A ratio decreases (Burgin et al., 1990; Brocke et al., 1995); these two findings are counter to what one would expect if NR2B and CaMKII were selectively co-regulated and co-functioning. Interestingly, calcium-independent CaMKII activity regulates the ability to induce LTD in hippocampal and cerebellar slices from adult animals, independent of NMDA receptor composition (Mayford et al., 1995; Hansel et al., 2006). Combined, these findings suggest that the NR2 subunit switch is not the sole factor that guides the late postnatal changes in synaptic plasticity. Inconsistencies in this and other models make obvious the complexity of the developmental regulation of plasticity induction. Other factors that likely explain these inconsistencies are developmental changes in upstream factors that influence NMDA receptor activation, including changes in baseline neurotransmission (excitatory and inhibitory), excitability, and short-term plasticity. Factors that lie downstream from NMDA receptor activation are primarily age-related changes in the expression and activity of postsynaptic signaling proteins. In parallel to NMDA receptor-dependent plasticity, additional presynaptic components to LTP expression are present at immature fore-brain synapses and dissipate with maturation (Foster and McNaughton, 1991; Larkman et al., 1992; Velisek et al., 1993; Williams et al., 1993; McNaughton et al., 1994; Lauri et al., 2007).

Short summary

The composition of NMDA receptors changes during postnatal periods when synaptic plasticity is modified. Early in development these receptors contain NR2B subunits. As neural systems mature, NMDA receptors with NR2A sub-units predominate. The shift from NR2B to NR2A changes many NMDA receptor properties, including synaptic targeting, ability to conduct calcium, and intracellular signaling. Focus has been on the change in calcium conductance and summation of synaptic responses that occur with substitution of NR2B with NR2A. Recent data supports an important influence of the intracellular carboxy terminus that is more closely associated with synaptic targeting and intracellular signaling than with calcium conductance. Prior models de-emphasize extra-NMDA receptor factors such as upstream and downstream effectors that likely influence plasticity induction and the differential expression of NMDAR-independent plasticity at different postnatal ages.

Other Developmental Factors That Influence the Threshold for Plasticity Induction

Upstream influences: glutamate release probability, short-term plasticity, AMPA receptor density/function, inhibitory transmission

The primary properties of excitatory and inhibitory synapses undergo modification beyond the end of the second postnatal week. After initial establishment, excitatory synapses become strengthened on both the pre-and postsynaptic sides, influenced in part by activity (De Simoni et al., 2003). In parallel, short-term synaptic plasticity is altered from the third to the fifth postnatal week at both cortical (Ramoa and Sur, 1996) and hippocampal synapses (Dumas and Foster, 1995). Also, [gamma]-amino-butyric acid (GABA) transmission shows age-related changes beyond P12, when it shifts from being excitatory to inhibitory (Ben-Ari et al., 1997). All of these developmental alterations, and other upstream factors, have the capacity to modulate the developmental shift in the threshold for plasticity induction. This section describes some synaptic processes acting upstream from NMDA receptor activation that change during the developmental period when the threshold for plasticity induction changes.

Glutamate release probability. Developmental alterations in the ability to induce LTP may be influenced by the basic growth in synaptic strength. This notion arises from the cooperative nature of LTP induction (McNaughton, 1982). That is, a minimum number of synapses must be activated to produce the postsynaptic depolarization necessary to activate NMDARs. Both the number of synapses and the strength of individual synapses increase during postnatal development. Transmitter release levels at SC-CA1 synapses increase from the third to the fifth postnatal week (in rats, Dumas and Foster, 1995; in mice, Dumas, 2010). One might suspect that increased transmitter release probability would facilitate LTP induction by enhancing NMDAR activation. Indeed, when multiple induction frequencies/protocols are tested, it is clear that LTP induction threshold decreases at the end of the third postnatal week (Dumas, 2010). It should be noted that in adult hippocampal slices, the probability of baseline transmitter release has been shown to be inversely related to the overall magnitude of LTP, but unrelated to the magnitude of increase in postsynaptic efficacy (Foster and McNaughton, 1991; Larkman et al., 1992; Palmer et al., 2004), suggesting no link between initial release probability and NMDAR-dependent LTP induction. Unfortunately, these studies were interested in the relationship between baseline presynaptic function and the mechanisms for LTP expression, not in induction, and they applied induction protocols that were insufficient for a full analysis of the relationship between baseline release probability and LTP induction sensitivity.

Short-term synaptic plasticity. Paired-pulse facilitation (PPF) is a short-term form of synaptic plasticity that reflects an increase in transmitter release probability produced by residual calcium in the presynaptic terminal and dissipates across the first 500 ms or so after an initial activation (Zucker and Regehr, 2002). At SC-CA1 synapses in the hippocampus, in parallel with the developmental increase in baseline transmitter release probability, PPF is reduced with increasing age (Dumas and Foster, 1995; Dekay et al., 2006; Speed and Dobrunz, 2008; Dumas, 2010). The net effect of a decrease in synaptic facilitation is analogous to the effect of decreasing NR2A content on synaptic summation at visual cortical synapses during 40 Hz stimulation (Philpot et al., 2007). Thus, in similar ways, changes in presynaptic facilitation and postsynaptic summation might alter LTP induction. However, opposite to developmental changes in facilitation in the hippocampus, PPF in visual cortex increases with increasing postnatal age (Angulo et al., 1999; Kumar and Huguenard, 2001). Therefore, contrary to what one might predict, there appears to be a relationship between the changes in facilitation and LTP induction threshold with increasing age across forebrain structures (cortex: PPF increases as LTP threshold increases; hippocampus: PPF decreases as LTP induction threshold decreases). If one considers PPF as an inverse index for transmitter release probability (Creager et al., 1980: Wu and Saggau, 1994), this putative relationship makes more sense (cortex: release probability decreases as LTP threshold increases; hippocampus: release probability increases as LTP induction threshold decreases). While the relationship between PPF and LTP induction has not been formally tested, only one line of seven separate lines of knockout mice that show alterations in PPF displays a change in LTP (Rosahl et al., 1993; Silva et al., 1996; Matilla et al., 1998; Moresco et al., 2003; Paterlini et al., 2005; Moretti et al., 2006). However, the protocol used to examine LTP in these studies, namely 100 Hz for 1 s, is likely above the range to adequately examine differential sensitivities in induction threshold. Protocols using lower, peri-threshold frequencies are necessary to observe relationships between presynaptic facilitation and LTP induction.

AMPA receptor density/function. AMPA receptors are added to the postsynaptic density with increasing age (Liao et al., 1999; Petralia et al., 1999, 2005). in parallel with a decrease in the numbers of silent synapses (displaying NMDA receptor, but not AMPA receptor responses) (Durand et al., 1996). Developmental alterations in the ability to induce LTP may be affected by this basic growth in postsynaptic strength. Stronger synapses having more AMPA receptors would more easily provide the necessary depolarization to activate NMDA receptors. Using an induction protocol of weak intensity, pairing presynaptic activity with a short postsynaptic burst of APs, LTP of increasing magnitude is observed from P9 to P22 (Meredith et al., 2003). Likewise, we have found that primed-burst potentiation, another minimal LTP induction protocol (Diamond et al., 1988), is absent at hippocampal synapses in juvenile mice but not in young adults (Dumas, 2010), suggesting that the threshold for LTP induction decreases as baseline postsynaptic responsiveness increases at hippocampal SC-CA1 synapses. To the contrary, in the visual cortex, eyelid parting is associated with global downscaling of excitatory postsynaptic current magnitude (Desai et al., 2002). Therefore, the threshold for LTP induction may shift in opposite directions in the visual cortex and hippocampus due, in part, to opposing changes in baseline postsynaptic strength.

Inhibitory transmission. Antagonists of inhibitory synaptic transmission have been shown to regulate the threshold for plasticity induction at adult cortical and hippocampal synapses. For instance, pharmacological blockade of [GABA.sub.A] receptors facilitates LTP and LTD induction (Kerr and Abraham, 1995; Wagner and Alger, 1995; Chapman et al., 1998). Additionally, [GABA.sub.A] receptor agonists increase the magnitude and range of induction frequencies that elicit LTD in hippocampal slices (Steele and Mauk, 1999). Clearly, there is reason to suspect that changes in inhibitory synaptic transmission during the late postnatal period alter the threshold for plasticity induction at cortical and hippocampal synapses.

In parallel to alterations in excitatory synaptic function, beyond the end of the second postnatal week there are changes in fast [GABA.sub.A] inhibitory synaptic transmission that could influence the threshold for plasticity induction. For instance, mRNA levels for the [GABA.sub.A] [alpha]1 subunit increase in cortex and hippocampus during the third postnatal week (Gambarana et al., 1990). In parallel, [GABA.sub.A] transmission matures during the third postnatal week, shown in acutely prepared hippocampal and cortical slices (Banks et al., 2002; Morales et al., 2002; De Simoni et al., 2003; Jiang et al., 2005), and subsynaptic [GABA.sub.A] receptors are not as fully occupied by quantal release at P15-21 as in adults (Cohen et al., 2000). In the visual cortex, an activity-dependent increase in GABAergic transmission occurs during the critical period (Hensch et al., 1998; Chattopadhyaya et al., 2004) and may act to prevent runaway potentiation. These data indicate that GABAergic synapses are developmentally weaker during the age when the threshold for LTD induction is low in visual cortex. However, the developmental growth of inhibitory synaptic transmission likely does not explain or relate to the decrease in LTP induction threshold observed late postnatally in the hippocampus. Similar to the logic applied to the NMDA receptor subunit switch, a single mechanism (development of inhibitory synaptic transmission) cannot explain the differenlial development of LTP induction in the cortex and hippocampus. Developmental changes in inhibitory synaptic transmission may thus not globally regulate plasticity induction threshold, but should be taken into account when attempting to describe the factors that limit LTD and cortical LTP induction with increasing age.

Other upstream factors--kinases, ion channels, metabotropic receptors. Other upstream factors are possibly involved in regulating the maturation of synaptic plasticity, including protein kinase C (PKC; MacDonald et al., 2001), hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels (Johnston and Narayanan, 2008), and metabotropic ligand-gated receptors (glutamate, mGluR; acetylcholine, mAChR: Abraham, 2008). Thought to play a role in promoting stability of enhanced synaptic efficacy after LTP induction (Angenslein and Staak, 1997), PKC can be considered a downstream factor. Involvement of PKC in neuronal excitability (Franceschetti et al., 2000; Okada et al., 2004) and experience-dependent modification of neuronal excitability (Sanchez-Andres and Alkon, 1991) makes this kinase an upstream factor as well. PKC translocation away from the CA1 pyramidal cell body occurs at the end of the second postnatal week in rats, at an age when these cells begin to show AP bursting upon membrane depolarization (Sanchez-Andres et al., 1993). This transition likely impacts synaptic plasticity by increasing NMDA receptor activation during suprathreshold (sufficient depolarization to cause APs) synaptic activation. Involvement of PKC in developmental alterations in synaptic plasticity has not been investigated.

Intrinsic membrane properties in resting neurons do not change appreciably after the end of the second postnatal week, when hippocampal synaptic plasticity is maturing (Spigelman et al., 1992; Dumas and Foster, 1995). However, this does not rule out influences of voltage-gated ion channels during plasticity induction. One interesting candidate in this regard is the HCN channel. HCN channels affect excitability in two main ways. First, they cause the membrane potential to depolarize slightly in the face of hyper-polarization, keeping it closer to AP discharge threshold; and they tend to shunt dendritic excitation, weakening the impact of synaptic excitation at the soma. Postnatal changes in expression and function of HCN channels in CA1 pyramidal cells might relate to changes in plasticity induction by changing rhythmic activity. HCN channel density in hippocampal CA1 pyramidal neurons decreases from 2 to 3 weeks of age. A resulting reduction in dendritic shunting could explain the concomitant reduction in LTP induction threshold. In neonates, HCN2 and HCN4 subunits are expressed and form channels that are highly sensitive to cAMP and have slower channel dynamics. During the third postnatal week, HCN channels contain predominantly HCN1, which produces faster channel dynamics and less sensitivity to cAMP (Surges et al., 2006). In parallel, CA1 population activity transitions from one that generates more low-frequency rhythms associated with high discharge rates in individual pyramidal cells, to one that generates higher frequency rhythms (theta, 4-14 Hz) with more moderate discharge rates in single cells. These data fit nicely with the parallel reduction in LTP induction threshold, suggesting that plasticity induction in the hippocampus is tuned to ongoing rhythms and discharge rates. Examination of possible relationships between developmental changes in HCN channels and plasticity induction is an open area for research.

Low-frequency induced LTD induction requires activation of mGluRs in developing hippocampus (Overstreet et al., 1997; Nosyreva and Huber, 2005), while LTD induced by repeated paired-pulse stimulation in adult hippocampal slices instead involves NMDA receptors (Oliet et al., 1997; Kemp et al., 2000). Likewise, evidence supports the involvement of modulatory neurotransmitters in cortical plasticity (Kirkwood et al., 1999; Yang et al., 2002; Granado et al., 2008; Scheiderer et al., 2008), suggesting alternative means to regulate plasticity induction under different developmental states of arousal or attention. A full description of other modulatory candidates is beyond the scope of this review. However, examination of developmental alterations in arousal and attention systems in relation to plasticity induction in the cortex and hippocampus could yield important insights into the regulation of activity-dependent synaptic plasticity (Singer, 1982).

Downstream influences: developmental alterations in postsynaptic kinases and phosphatases

Many of the protein kinase and phosphatase signaling cascades involved in the induction of synaptic plasticity have been well described (Soderling and Derkach, 2000; Colbran, 2004). To summarize, the main core of kinases and phosphatases includes CaMKII, PKA, protein phosphatase 1 (PP1), and protein phosphatase 2b (PP2b, calcineurin) (Fig. 5). CaMKII and PKA are both activated by CaM following calcium entry into postsynaptic spines. (PKA is activated indirectly via CaM association with adenylate cyclase [AC] and the production of cAMP.) Once phosphorylated by CaM, CaMKII autophosphorylates and, in this fashion, remains active long after the CaM signal has terminated. Among its many functions, autophosphorylation and continued activation of CaMKII are thought to support the first hour of LTP expression in adults (Lisman et al., 2002). PP1 acts to dephosphorylate and inactivate CaMKII. However, this does not happen immediately, due to CaMKII-and PKA-dependent activation of inhibitory protein 1 (I-1) and subsequent inhibition of PP1 activity. CaMKII also inactivates calcineurin, further tipping the kinase/phosphatase balance in the direction of kinase activation. In contrast, during low-frequency synaptic stimulation, calcineurin is selectively activated by CaM, allowing it to dephosphorylate I-1, which ultimately results in dephosphorylation and deactivation of CaMKII by PP1. Weak synaptic stimulation may preferentially activate calcineurin because this phosphatase is activated by lower levels of CaM activity than is CaMKII (Lisman, 1989; Colbran, 2004). It is the overall balance of kinase to phosphatase activity which is presumed to govern the direction of change in synaptic efficacy, with greater kinase activity promoting potentiation and greater phosphatase activity promoting depression.


Developmental alterations in the expression and activity of these plasticity-related kinases and phosphatases influence the induction of synaptic plasticity. Induction of LTP depends on an increase in CaMKII and PKA activity as a result of increased intracellular [Ca.sup.2+] levels. There is a developmental shift in the expression of these kinases during the postnatal time period when LTP and LTD are altered. In the hippocampus, CaMKII expression is very low until the end of the first postnatal week and reaches adult levels by the end of the third postnatal week (Burgin et al., 1990; Brocke et al., 1995), while PKA expression is at a stable peak during the second postnatal week and declines to adult levels by the end of the third week (Li et al., 2003). Developmental changes in kinase expression might explain the differential phosphorylation states of AMPA receptor subunits at different postnatal ages (Li et al., 2003) and fit well with the age-related changes in the mechanisms for LTP expression (Wikstrom et al., 2003; Yasuda et al., 2003).

The developmental decline in LTD is not mirrored by decreases in phosphatase expression. To the contrary, although PP1 expression and activity by itself does not show late postnatal changes, I-1 expression decreases across the third postnatal week in whole-brain homogenates (Sakagami et al., 1994; Dudek and Johnson, 1995). This reduces the negative contraint on PP1 imposed by PKA and CaMKII activity (Fig. 5). In addition, calcineurin expression in the hippocampus increases from the end of the second postnatal week to adulthood (Eto et al., 2008) and differentially regulates mGluR-and NMDAR-dependent LTD, inhibiting presynaptic group II mGluR-dependent LTD, and facilitating postsynaptic NMDAR-dependent LTD (Li et al., 2002). Interestingly, a developmental decrease in calcium-independent CaMKII activity does parallel the postnatal reduction in LTD (Molloy and Kennedy, 1991). Previous work indicates that re-establishment of calcium-independent CaMKII activity in adult transgenic mice produces a juvenile phenotype at hippocampal synapses and facilitates LTD induction (Mayford et al., 1995). Therefore, while an increase in calcium-dependent CaMKII activity likely supports the shift in the mechanisms for LTP expression, a parallel reduction in calcium-independent CaMKII activity may regulate the developmental decline in the ability to induce LTD. Additionally, forebrain expression of the phosphatase-binding protein spinophilin (neurabin-2) increases from the end of the first to the end of the third postnatal week and declines to adult levels by the end of the first postnatal month (Allen et al., 1997). Numerous phosphatase-binding proteins regulate the function of plasticity-related phosphatases (Colbran, 2004) and should be considered when studying the developmental regulation of synaptic plasticity.

Long-lasting modifications in synaptic efficacy that act in parallel with NMDAR-dependent long-term potentiation

Although this review focuses on NMDA receptor-dependent synaptic plasticity, it is important to note that other forms of lasting synaptic plasticity exist and also show developmental modification. For instance, earlier research on the mechanisms of LTP expression revealed a form of LTP in developing hippocampus that was not blocked by NMDA receptor antagonists (Velisek et al., 1993). It was also noted that (a) presynaptic LTP expression was enhanced at synapses that had low baseline estimates of presynaptic function (Foster and McNaughton, 1991; Larkman et al., 1992) and (b) pharmacological treatments that affected presynaptic kainate receptors (Lauri et al., 2007) or presynaptic kinase signaling (AC and PKA) produced a more pronounced long-lasting increase in synaptic efficacy in hippocampal slices from juvenile rats compared to adults (Chavez-Noriega and Stevens, 1992, 1994; Dumas, 2005a). Recently, it was shown that the threshold for presynaptic LTP increased during late postnatal development, in relation to an increase in baseline transmitter release probability (Dumas, 2010). Finally, LTD induction is supported primarily by activation of metabotropic glutamate receptors in juvenile hippocampal slices and by NMDA receptors in slices from more mature animals (Overstreet et al., 1997; Nosyreva and Huber, 2005). Combined, these findings support the notion that immature synapses exhibit a greater variety in the types of lasting synaptic plasticity that are expressed. As a result, it is unlikely that developmental changes in the overall magnitude of LTP or LTD solely reflect changes in NMDA receptor function.

Short summary

Aside from NMDAR composition, many other aspects of synaptic physiology are altered as LTP and LTD are developmentally modified. Upstream effectors include factors that regulate NMDAR activation such as transmitter release levels, AMPA receptor number and function, short-term synaptic plasticity, inhibitory synaptic transmission, and channels and kinases that regulate neuronal excitability. Downstream factors impacted by NMDA receptor activation that show developmental alterations in agreement with the changes in LTP and LTD induction include levels of active (calcium-insensitive) and calcium-sensitive CaMKII, PKA, and phosphatase-binding proteins. In addition, parallel processes that are not directly related to NMDA receptors, like presynaptic forms of LTP induced by kainate receptor or AC/PKA activation and LTD that is dependent on metabotropic glutamate receptors, are present early in development and dissipate as neural circuits mature. Models of the developmental regulation of synaptic plasticity that do not consider these factors are incomplete.


Following synapse overpopulation, determination of maintenance or loss of individual synapses relies on their activity states. Activity-dependent functional plasticity at glutamatergic synapses is critical for the proper wiring of neurons during development (Bear et al., 1987; Constantine-Paton et al., 1990; Kandel and O'Dell, 1992) and for network modifications that support associative learning and memory in adults (McNaughton and Barnes, 1990; Moser and Moser, 1998; Shapiro and Eichenbaum, 1999). During late postnatal forebrain development, glutamatergic synaptic plasticity is altered, resulting in more stable neuronal networks with better information processing capabilities (as shown by improved perceptual and cognitive abilities in behavioral studies). While many of the mechanisms that support LTP and LTD in adults have been elucidated, the developmental factors that regulate the maturation of plasticity induction and expression, and therefore the factors that control network organization, remain largely unknown.

In addition to the modifications in the structure and function of NMDARs--the central focus for synaptic plasticity--changes in both upstream and downstream factors may be equally important in determining the threshold for plasticity induction (Fig. 6). Of the many processes that compose baseline synaptic transmission, an increase in synaptic AMPA receptor number has the potential to explain the changes in LTP induction and expression with increasing age. Interestingly, the magnitude of the synaptic responses mediated by AMPA receptors changes in opposite directions in the visual cortex and hippocampus, as does the shift in the induction threshold for LTP, producing an inverse relationship between baseline postsynaptic responsiveness and LTP induction threshold in both structures. The same can be said for opposing changes in transmitter release levels in the cortex and hippocampus in relation to the threshold for plasticity induction. Additionally, short-term plasticity is likely more than an epiphenomenon of plasticity induction protocols and may influence NMDAR activation and plasticity induction. Downstream from the NMDAR, protein kinases and phosphatases essential for LTP and LTD show developmental alterations in expression and function. Opposite changes in PKA and CaMKII expression observed during the third postnatal week in the hippocampus are likely to at least partially explain the developmental shift in the specific kinase dependence of LTP, although the implications for induction threshold are not clear. By inhibiting CaMKIl, postnatal increases in PP1 and calcineurin activity provide a possible explanation for decreased LTP magnitude with age, while a decrease in calcium-independent CaMKII activity may underlie the decrease in the ability to induce LTD.


Integration of the findings in this review demonstrates the complex regulation of neural network formation and highlights some profound modifications in activity-dependent plasticity at glutamatergic synapses. Further gains in understanding neural network formation will come from experiments that examine the effects of age-related changes in mechanisms up- and downstream from NMDAR activation that control the induction and expression of synaptic plasticity. Moreover, a more detailed understanding of the factors that govern the development of synaptic plasticity and how they change in accord with emerging perceptual and cognitive abilities will help to distinguish plasticity mechanisms that are more closely related to network assembly from those that more directly support information processing. Finally, regulation of synapse number in developing neural networks overlaps with determination of cell survival/death in tissues (Ceulemans and Bollen, 2004; Li et al., 2010); and on a more abstract level, these processes likely share fundamental rules with processes that control organism fate in populations, suggesting that basic ideas presented in this review may be scalable.


We thank Giorgio Ascoli for providing critical evaluation. This research was supported by funds from the Krasnow Institute for Advanced Study at George Mason University and by a Multiple University Research Initiative award from the Department of Defense (ONR# N00014-10-1-0198).

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EMILY T. STONEHAM (1), (2), *, ERIN M. SANDERS (1), (2) *, MOHIMA SANYAL (2), AND THEODORE C. DUMAS (1), (2), [dagger]

(1) Molecular Neuroscience Department, (2) Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia 22030

Received 16 November 2009; accepted 5 August 2010.

* These authors contributed equally to this project.

[dagger] To whom correspondence should be addressed, at Molecular Neuroscience Department, 4400 University Drive, MS 2A1, Fairfax, VA 22030;

Abbreviations: AC, adenylate cyclase; AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; AP, action potential; CaM, calmodulin; CaMKII, calmodulin-dependent kinase II; EPSP, excitatory postsynaptic potential; HCN, hyperpolarization-activated cyclic nucleotide-gated cation; I-1, inhibitory protein 1; LTD, long-term depression; LTP, long-term potentiation; NMDA, N-methyl-D-aspartate; P, postnatal day; PKC, protein kinase C; PP1, protein phosphatase 1; PPF, paired-pulse facilitation; SC-CA1, Schaffer collateral synapse.
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