Transient Synaptic Potentiation in the Visual Cortex. II. Developmental Regulation
Krisztina Harsanyi and
Michael J. Friedlander
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
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ABSTRACT |
Harsanyi, Krisztina and Michael J. Friedlander. Transient synaptic potentiation in the visual cortex. II. Developmental regulation. J. Neurophysiol. 77: 1284-1293, 1997. In our previous study, pairing-induced transient synaptic potentiation in supragranular layers of the visual cortex was described in mature guinea pigs. In the present study, the development of this type of synaptic plasticity and the underlying cellular mechanisms that mediate it were evaluated in animals from postnatal day (PND) 5 to 180. Potentiation is more reliably evoked in younger animals (likelihood: 75%, PND 5-30; 51%, PND
34), and the magnitude of the effect is greater (+40 ± 3%, mean ± SE, PND 5-30; +26 ± 3%, PND
34). Similar to data obtained from the mature animals, visual cortical transient synaptic potentiation in the immature cortex occurs at excitatory synaptic sites directly activated by the stimulation, and activation by local recurrent cortical circuits is not necessary for the induction of this potentiation. This is demonstrated by 1) experiments in which action potential output from the paired neuron was blocked by Lidocaine, N-ethyl bromide quaternary salt applied into the neuron (5 of 5), and 2) experiments in which the contribution to the compound postsynaptic potential by inhibitory synapses was eliminated by selective, intracellular blockade of
-aminobutyric acid-mediated inhibitory postsynaptic potentials only onto the recorded neuron (7 of 11). Thus these perturbations do not reduce the likelihood or magnitude of this synaptic potentiation. In contrast to the N-methyl-D-aspartate (NMDA) receptor dependence for induction of this synaptic potentiation in the cortex of mature animals, in the young animals' cortices (PND 11-27) potentiation is readily induced during blockade of NMDA receptors (72%, 13 of 18, not different from control: 75%, 40 of 53). Thus the NMDA receptor becomes functionally linked to a synaptic potentiation cascade during development, replacing another 2-amino-5-phosphonovaleric acid (APV)-insensitive potentiation process in the neonatal cortex. Postsynaptic intracellular calcium has a critical role in the induction of this form of synaptic potentiation in all ages studied. Synaptic potentiation was prevented (8 of 11 cases) or was replaced by synaptic depression (3 of 11 cells) in experiments in which postsynaptic calcium levels were reduced by intracellular application of 1,2-bis-2-aminophenoxy ethane-N,N,N
,N
-tetraacetic acid (BAPTA) in the cortex of young (PND 7-14) animals, or in which the extracellular calcium concentration was lowered. Inhibition of postsynaptic calcium-induced calcium release blocked synaptic potentiation (4 of 4 cells). Prolonged superfusion (3 h) of the nitric oxide synthase inhibitor L-nitro-arginine (LNA) did not significantly affect the likelihood (in LNA, 81%; 13 of 16 cells), or the magnitude (+38 ± 7% increase in LNA vs. +40 ± 3% in control cases) of potentiation, in contrast to its effects in the mature cortex.
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INTRODUCTION |
The effects of sensory input and afferent activity on the development of perceptual function and the architecture of the cerebral cortex (Hubel and Wiesel 1970
) are well established. The primary visual cortex has served as a particularly useful system for the study of experience-dependent modification of synaptic structure and function (Wiesel 1982
). Relatively brief intervals (Freeman and Ohzawa 1988
) of imbalanced binocular vision during critical periods of postnatal development (Daw et al. 1992
) can lead to dramatic and long-lasting differential responsiveness of cortical neurons to inputs from the competitively advantaged and disadvantaged afferents, respectively, and to differences in the structure of those afferents and their synapses in the visual cortex (Antonini and Stryker 1993
; Friedlander et al. 1991
).
Although the end points of these experimental manipulations are well characterized, the processes that occur during the imbalanced afferent activity are less fully understood. The long-term modification of cortical synaptic strength and structure must reflect changes that occur during development when certain pathways are selectively stabilized at the expense of others (LeVay et al. 1978
). Activity-dependent homosynaptic potentiation and hetero- and homosynaptic depression have been posited as processes that may contribute to the long-term strengthening and weakening of cortical synapses, respectively, during development (Bienenstock et al. 1982
; Clothiaux et al. 1991
; Dudek and Friedlander 1996b
; Kirkwood et al. 1995
; Tsumoto 1992
). One construct that has been used to predict how the successful repeated activation of postsynaptic visual cortical neurons by afferents in vivo may lead to enhanced synaptic efficiency and how the unsuccessful activation of postsynaptic neurons by afferents may lead to reduced synaptic efficiency is the Bienenstock, Cooper and Munro model (Bear et al. 1987
; Bienenstock et al. 1982
; Fregnac et al. 1994
; Kirkwood et al. 1996
; Shulz and Fregnac 1992
). Application of protocols that pair synaptic activation with postsynaptic depolarization in vitro in the mature cortex (Fregnac et al. 1994
; Harsanyi and Friedlander 1997
) leads to specific transient enhancement of the activated excitatory synapses. Moreover, pairing synaptic activation with postsynaptic hyperpolarization in the mature cortex leads to transient synaptic weakening (Fregnac et al. 1994
). However, if these processes contribute to the long-term modification of synaptic structure and function that occur as a result of differential patterns of activation, they must be active during postnatal development and show some degree of developmental regulation.
In the previous report (Harsanyi and Friedlander 1997
) we evaluated the cellular mechanisms and sites of action of transient synaptic potentiation induced by low rates of repetitive brief periods of coincident synaptic activation and postsynaptic depolarization in the visual cortex of mature guinea pigs. In the present study, the capacity for the induction of this type of plasticity and its underlying mechanisms are evaluated during postnatal development.
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METHODS |
Preparation of slices
Experimental procedures have been described in detail previously (Fregnac et al. 1994
; Harsanyi and Friedlander 1997
). Briefly, visual cortical slices were obtained from deeply anesthetized pigmented guinea pigs (PND 30 or younger). Coronal slices (400 µm thick) containing the primary visual area were cut with a vibroslicer (Campden Instruments, London, UK) in ice-cold artificial cerebrospinal fluid (ACSF). Slices were transferred into a humidified interface-type recording chamber (Medical Systems, Greenvale, NY). The temperature was maintained at 35°C. Additional slices were kept at room temperature in artificial ACSF for <5 h with the use of an oxygenated holding chamber (Medical Systems, Greenvale, NY).
Solutions
The ACSF consisted of (in mM) 124 NaCl, 2 KCl, 2 MgSO4, 2 CaCl2, 1.25 KH2PO4, 26 NaHCO3, and 11 glucose, pH maintained at 7.4 by saturating the solution with 95% O2-5% CO2. The superfusion rate was 1 ml/min. The N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (DL-APV; Sigma, St. Louis, MO), and the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine (Sigma) were dissolved in ACSF and were bath applied. In some experiments, only the D isomer of APV was used, and this gave similar results to those obtained in experiments in which the DL form was used.
Stimulation and recording
Recording micropipettes were pulled from glass capillary filaments (1.5 mm OD, 0.86 mm ID; A-M Systems) with a horizontal puller (Sutter Instruments, San Rafael, CA). Pipettes were filled with 2.0 M potassium acetate (pH adjusted to 7.1 with 1.0 M acetic acid) and had resistances between 90 and 140 M
. In certain experiments, 100 mM N-ethyl bromide quaternary salt (QX-314; Research Biochemicals, Natick, MA) or 200 mM 1,2-bis-2-aminophenoxy ethane-N,N,N
,N
-tetraacetic acid (BAPTA; Sigma, St. Louis, MO) was included in the pipette filling solution. In some experiments, inhibitory postsynaptic potentials (IPSPs) were intracellularly blocked by filling the recording micropipettes with the chloride channel blocker 5,11,17,23-tetrasulfonato-25,26,27,27-tetramethoxy calix[4]arene (TS-TM-calix[4]arene; 3 µM) (Dudek and Friedlander 1996a
) dissolved in 1.0 M cesium acetate. Bipolar stimulating electrodes (FHC, Brunswick, ME) were positioned at the white matter/layer VI border. Recording micropipettes (resistance 90-150 M
) were placed in the supragranular cortical layers, in beam with the stimulating electrode. Conventional intracellular recordings were obtained with an Axoclamp 2 A amplifier (Axon Instruments, Foster City, CA) in bridge mode. Data were digitized at 4 kHz and collected on a Macintosh II computer. Analysis of data took place on-line and off-line, with the use of customized software. The intensity of stimulation (pulse generator: Master 8; AMPI, Jerusalem, Israel) through the bipolar electrode was adjusted to evoke postsynaptic potentials (PSPs) of 30-35% of the value required to obtain an action potential. Frequency of the afferent stimulation was 0.1 Hz throughout all experiments. In a baseline period (10-20 min), this low-frequency stimulation (50 µs, 30-100 µA) was delivered through the bipolar electrode and PSPs were recorded from a layer II/III neuron. During pairing protocols (60 pairings over 10 min at 0.1 Hz), intracellular postsynaptic depolarizing current pulses (duration 80 ms; intensity +0.5 to +2.8 nA) delivered to the neuron were paired with coincident presynaptic stimulation (following the onset of the depolarizing current pulse with a 25-ms delay). Control stimulation and recording of PSPs were resumed in the postpairing period.
Data analysis
The start of the PSP was defined as the point in which the recorded voltage was >2 SD from the baseline. The highest point of the PSP was considered as the peak amplitude. PSP peak amplitude, initial slope (slope in the 1st ms of the PSP), slope to peak (slope of the PSP between 10 and 90% of the peak amplitude), and half-width measured at half-height of the PSP were measured on-line and off-line. Unpaired t-test statistics (2-tailed) were used to determine significant effects (P value set at 0.05) on the different aspects of the PSPs. Series of t-tests were carried out on a given experiment. For purposes of statistical analysis, the last 30 PSPs (5 min preceding the pairing period) of the baseline were regarded as a control group. t-Tests were conducted on the first 12 postpairing trials; then the analysis moved forward in 1-min increments. With this "sliding window" method, we evaluated the existence and time course of significant potentiation quantitatively. Uncorrected
2 test determined the significance of effects on the likelihood of transient potentiation.
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RESULTS |
Transient synaptic potentiation in the early postnatal period
The study was carried out for an additional 49 supragranular neurons (53 pairing tests; Table 1) in primary visual cortex of guinea pigs (PND 5-30). Basic membrane characteristics of the tested neurons are summarized in Table 1. The experiment illustrated in Fig. 1A is representative of transient synaptic potentiation in a cortical neuron from a PND 22 animal, an experiment that in many respects is similar to those in older animals. In some cases, however, potentiated synaptic transmission persisted for considerably longer periods (>90 min; Fig. 1B) as in this neuron from a young animal (PND 8). The ensemble average of PSP peak amplitudes (mean ± SE) from experiments carried out in cortical slices obtained from animals in the first 2 wk of postnatal life (n = 18) is illustrated inFig. 1C.

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| FIG. 1.
Transient synaptic potentiation in cortical neurons from young animals. A: induction of synaptic potentiation in a neuron from a postnatal day (PND) 22 animal [resting membrane potential (Er): 89 mV; input resistance (Rin): 60 M with the use of +2.0-nA intracellular depolarizing pulses. The pairing paradigm evoked potentiation of the postsynaptic potential (PSP) peak amplitude (top; +69% enhancement), and the "slope to peak" (bottom; +86% enhancement). A, right: averages of 30 PSPs from the pre- and postpairing period are shown superimposed. B: synaptic potentiation with an especially long duration from a PND 8 animal (Er: 85 mV; Rin: 47 M ). The PSP peak amplitude increased by +63% and the slope to peak increased by +48% after the pairing protocol (+1.7-nA pulses). Superimposed averaged PSPs, taken from time windows represented by the numbered lines, show the effect of pairing and subsequent recovery. Significant potentiation persisted for 90 min in this case. C: normalized means ± SE of 18 experiments in animals <2 wk of age.
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The results of evaluating the likelihood, magnitude, and duration of synaptic potentiation as a function of postnatal age are summarized in Fig. 2. Data from our parallel study on adult animals (
PND 34) are compared with results obtained from the young age group. Transient potentiation occurred in ~40% of the cells tested in the older animals, in agreement with our initial characterization of this phenomenon (Fregnac et al. 1994
). The results of the present study demonstrate that the incidence of potentiation is higher in young animals (Fig. 2A). Likewise, the magnitude of potentiation (Fig. 2B) is greater early in life (magnitude of PSP peak amplitude potentiation at PND 30 or younger: +40 ± 3%, mean ± SE; magnitude at older than PND 91: +25 ± 5%, P = 0.081). The magnitude of peak amplitude potentiation in young animals is also demonstrated in Fig. 3A, in which the actual pre- and postpairing peak amplitude values are shown. A cumulative histogram illustrating the normalized enhancement of the PSP peak amplitude in the significantly affected cases is shown in Fig. 3B.

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| FIG. 2.
Effects of postnatal age. A: frequency distribution histogram of likelihood of potentiation induction as a function of postnatal age. B: scatter plot of the magnitude of transient potentiation vs. age (all experiments included). C: scatter plot of the duration of potentiation vs. age. Data illustrated are only for the cells with significant potentiation of the PSP peak amplitude. In 1 experiment (*) the duration of effect (150 min) was greater than the maximum value indicated on the vertical axis.
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| FIG. 3.
Analysis of the magnitude of transient synaptic potentiation in young animals. A: scatter plot illustrating the actual pre- and postpairing PSP peak amplitude values for experiments in which the pairing protocol resulted in significant synaptic potentiation (n = 40) for cases in animals PND 30 and younger. Diagonal line: case in which pre- and postpairing amplitude are equivalent. B: cumulative histogram of the magnitude of the PSP peak amplitude potentiation (n = 40) for cases in animals PND 30 and younger.
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In most cases the PSP peak amplitude was potentiated. However, in many cases the pairing protocol also led to a significant increase in the initial slope, the slope to peak, and/or the half-width measured at half-height of the PSPs (see Table 2). In contrast to transient synaptic potentiation in the mature cortex (Fig. 3E in Harsanyi and Friedlander 1997
), there is a higher incidence for potentiation of the initial slope of the PSP in young animals (51%, n = 27 of 53 in PND 30 and younger vs. 24%, n = 22 of 92 in older than PND 30). This suggests that the early monosynaptic component of the PSP is more susceptible to transient synaptic potentiation by the pairing protocol in younger animals. The overall mean duration of the peak amplitude potentiation in animals PND 30 and younger is 27 ± 3 min, with some (n = 10) neurons from the youngest animals remaining potentiatiated for >30 min (Figs. 1, B and C, and 2C). This is in contrast to the potentiation induced in older animals, where synaptic efficiency rarely remained elevated beyond 30 min (Fig. 2C) (Figs. 3, 5, 6, and 9 in Harsanyi and Friedlander 1997
). Thus, although transient synaptic potentiation induced by a low-frequency pairing protocol is a robust phenomenon for many neurons in the mature visual cortex, it shows a developmental gradient with greater incidence, strength, and persistence in the younger cortex.

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| FIG. 5.
Synaptic potentiation in the presence of 2-amino-5-phosphonovaleric acid (APV). Individual examples of transient synaptic potentiation while APV is in the superfusate are shown in A, B, and D. A: bath application of APV (50 µM) started 40 min before the beginning of the experiment. The pairing protocol (+2.8-nA pulses) induced potentiation of the PSP peak amplitude (+24% increase) even in the presence of APV. Potentiation of the responses persisted for 35 min (Er: 83 mV; Rin: 37 M ; PND 18). B: synaptic potentiation in another neuron (Er: 85 mV; Rin: 30 M ; PND 16) in normal artificial cerebrospinal fluid (ACSF) (1st pairing) and in APV (2nd pairing). The peak amplitude was potentiated by +26% (pairing pulses: +2.4 nA). The pairing paradigm was repeated 1 h after APV (50 µM) was introduced into the bath, and it also resulted in an increase (+20%) in the PSP peak amplitude. Arrows: point at which voltage dependence of the PSPs was tested (see C) both in ACSF and in APV. C: recordings from the same neuron as in B. Voltage dependence of the PSPs was evaluated in ACSF (left) and later in APV (right), at time points indicated by the arrows in B. PSPs were collected during depolarization (Em: 68 mV; top row), at rest (Er: 85 mV; middle row), and during hyperpolarization (Em: 95 mV, bottom row). Each trace represents an average of 5 PSPs. C, bottom: 2 averages taken at depolarized membrane potential are shown superimposed. Note the effect of APV on the late component of the PSP. D: example of transient potentiation induced in a neuron (Er: 82 mV; Rin: 65 M ; PND 11) by a pairing protocol (+2.3 nA pulses) in ACSF (1st pairing; +41% increase in PSP peak amplitude) and during APV application (2nd pairing; 28% increase). E: likelihood (black columns) of potentiation was not effected by the N-methyl-D-aspartate (NMDA) receptor blockade (72% in APV vs. 75% in ACSF). The magnitude of potentiation in APV (white columns: +26 ± 4% increase) was moderately reduced (P = 0.05) compared with control (+40 ± 3% increase).
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| FIG. 6.
Nitric oxide-independent synaptic potentiation. Horizontal bars: bath application of the nitric oxide synthase inhibitor L-nitro-arginine (LNA) (100 µM). A: 2 pairing protocols (+2.3- and +2.4-nA currents, respectively) were applied (Er: 78 mV, Rin: 40 M ), evoking a 60 and 48% increase in the PSP peak amplitude, respectively. The superfusion of 100 µM LNA was begun 6 h before the start of the experiment. B: overall proportion of cells that were able to be potentiated (black columns; 75% in control ACSF vs. 81% in LNA) was not different ( 2 = 0.23, P = 0.631). The average magnitude of potentiation (white columns) was also similar in the presence of LNA (+38 ± 7% vs. control +40 ± 3%; P = 0.787).
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| FIG. 9.
Transient synaptic potentiation during early postnatal development. Potentiation induction in the neonate is largely independent of NMDA receptor activation, because it occurs, although showing a slightly reduced magnitude, in the presence of APV. This plasticity is calcium dependent, and mechanisms that may lead to the postsynaptic calcium rise are shown in the drawing. Possible sources of calcium are glutamate receptor 2 subunit-lacking -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, voltage-gated calcium channels (VGCC), and the metabotropic glutamate receptor (M)-guanosine 5 -triphosphate binding protein (G)-phospholipase C (PLC)-inositol triphosphate (IP3) pathway. Further release of calcium from intracellular IP3- or ryanodine-sensitive calcium stores could amplify the postsynaptic signal.
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Site of plasticity
A series of experiments was carried out in the young animals to determine the site of potentiation induction within the local cortical network, as was done in mature animals (Harsanyi and Friedlander 1997
). Because the neuron that is directly depolarized by intracellular current injection usually fires action potentials during the pairing protocol, it was important to determine whether modifications responsible for the increased PSP amplitude occur at the activated synaptic sites on the recorded neuron or elsewhere in the cortical network. Thus we applied the lidocaine derivative QX-314 intracellularly to block action potential output from the activated neuron (Connors and Prince 1982
) during the pairing paradigm.
The results obtained in cortical slices from neonatal animals were similar to those in the adult. That is, synaptic potentiation was induced regardless of the presence of the blockade of spike output from the neuron that participated in the pairing (n = 5; data not shown). These results indicate that transient synaptic potentiation in the neonate, as in the adult, does not require action potential output from the neuron. Thus modification of synaptic efficiency occurs at synaptic sites on the cell directly activated by stimulation of the afferents.
We have shown in the mature cortex that transient synaptic potentiation is a result of true up-regulation of excitatory synaptic transmission (Harsanyi and Friedlander 1997
). To investigate whether this is true for the immature cortex, we blocked IPSPs only in the recorded neuron by applying intracellular cesium to block potassium currents, and a compound that blocks
-aminobutyric acid-A-mediated chloride currents by intracellular application, TS-TM-calix[4]arene (Dudek and Friedlander, 1996a
). The results obtained were similar to those of the mature cortex, that is, intracellular blockade of IPSPs only onto the recorded neuron did not prevent the occurrence of synaptic potentiation. An example of the effective blockade of early and late IPSPs 15 min after impalement is illustrated in Fig. 4A. Transient synaptic potentiation was obtained (Fig. 4, B and C) in 7 of 11 neurons (64%) from young animals with such intracellular blockade of synaptic inhibition. This likelihood of potentiation is not significantly different from the control 75% (
2 = 0.654,P = 0.419) in this age group. Thus, as in the adult, our pairing protocol in neonatal cortex induces an enhancement of compound PSPs by potentiating excitatory synaptic transmission at synaptic sites directly impinging onto the neuron that participates in the pairing.

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| FIG. 4.
Transient synaptic potentiation during intracellular blockade of inhibitory PSPs (IPSPs). Recordings were obtained with micropipettes filled with 5,11,17,23-tetrasulfonato-25,26,27,27-tetramethoxy calix[4]arene (TS-TM-calix[4]arene) (3 µM; see drawing) in cesium acetate (1.0 M) to block early -aminobutyric acid-A and late -aminobutyric acid-B mediated IPSPs, respectively. A: initially, the membrane potential of the neuron (PND 18) was depolarized by current injection to visualize the early IPSP. Bottom arrow: average of 10 PSPs with an apparent early IPSP at 5 min after the impalement of the cell (same as in B). The IPSP was eliminated in 15 min (top arrow). B: pairing protocol on the same cell (Em: 75 mV; Rin: 50 M ), with the use of +1.8-nA intracellular current pulses, induced potentiation (+45% enhancement) of the PSP. C: likelihood (black columns) of potentiation is not significantly different (64% vs. control 75%; 2 = 0.654, P = 0.419) when IPSPs were blocked by intracellular TS-TM-calix[4]arene/cesium. Magnitude (white columns) of potentiation during intracellular blockade of IPSPs did not differ significantly from control (+28 ± 5% vs. control +40 ± 3% increase; P = 0.21).
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Synaptic potentiation during blockade of NMDA receptors
NMDA receptors have been implicated in the induction of a wide range of types of plasticity in the CNS (Artola and Singer 1987
; Cline and Constantine-Paton 1990
; Collingridge et al. 1983
; Dudek and Bear 1992
; Morris et al. 1986
). Many reports (Cline and Constantine-Paton 1990
; Hahm et al. 1991
; Li et al. 1994
; Rabacchi et al. 1992
) indicate that NMDA receptor-mediated events play an important role in plasticity in the neonate, including visual cortical ocular dominance plasticity (Kleinschmidt et al. 1987
). Moreover, activation of NMDA receptors is necessary for the induction of transient synaptic potentiation by application of our low-frequency pairing protocols in the mature cortex (Harsanyi and Friedlander 1997
). Thus we evaluated the role of NMDA receptors in this type of synaptic plasticity as a function of postnatal age by the use of the competitive NMDA receptor blocker APV (50 µM) in the superfusate.
Surprisingly, although APV blocked induction of potentiation induction in the adult (Fig. 7 in Harsanyi and Friedlander 1997
), it did not consistently block the induction of transient potentiation (Fig. 5) in cortical slices from young animals (n = 5 of 18 cases; 28%). The inability of APV to block the effects of application of the pairing protocol in the cortex of young animals may be due to a lack of expression of conventional NMDA receptors (Laurie and Seeburg 1994
; Sheng et al. 1994
) at these ages. We tested for this possibility by evaluating the voltage dependence and pharmacological characteristics of the synaptic responses (Fig. 5C; same cell as in B; time of test runs indicated by arrows). A late component of the PSP is revealed with increasing depolarization (Fig. 5C, inset), suggesting that NMDA receptors are present and that they contribute to the generation of PSPs in the young animals as they do in the more mature animals. Moreover, this late, depolarization-dependent component of the PSP is blocked by 50 µM APV (Fig. 5C, inset). This indicates that, in young animals, transient synaptic potentiation in the presence of APV is not due to a lack of conventional functional NMDA receptors or to an inability of APV to block these NMDA receptors. It is worth noting that the induction of potentiation during APV application in young animals is accompanied by a small reduction in the average magnitude of potentiation (control +40 ± 3%; +26 ± 4% in APV, P = 0.05; see Fig. 5, D and E).

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| FIG. 7.
Transient synaptic potentiation in the neonatal cortex is calcium dependent. A: neuron (Er: 73 mV, Rin: 25 M ; PND 12) impaled with a micropipette containing the calcium chelator (see drawing) 1,2-bis-2-aminophenoxy ethane-N,N,N ,N -tetraacetic acid (BAPTA) (200 mM) was subjected to 2 pairing protocols (+2.1- and +2.5-nA depolarizing currents, respectively). The 1st pairing resulted in a small decrease in the average peak amplitude of the PSP ( 8%). The 2nd pairing epoch evoked a more substantial depression of the PSP ( 27% reduction). B: in no case (0 of 11) was potentiation of the PSPs observed when pairing protocols were conducted in the presence of intracellular BAPTA. The average change in PSP peak amplitude following the pairing protocol during intracellular chelation of calcium was a decrease by 7 ± 4% (see white columns). This is due to the 3 of 11 cases in which significant synaptic depression was detected after the pairing paradigm. C: effects of reduced extracellular calcium concentration ([Ca2+]o) on transient synaptic potentiation in the cortex from a young (PND 16) animal. After the baseline period, the pairing protocol (in this experiment +2.2-nA pulses were used in each case) induced a potentiation of the PSP peak amplitude (+89% increase). After recovery from this effect ( 30 min), superfusion of a low-calcium (1.0 mM) ACSF solution was begun. Note that the size of the baseline PSPs decreased gradually because of the low [Ca2+]o. A baseline was collected in the low-calcium solution, during which we increased the duration of the white matter afferent stimulation (1st arrow) from 50 to 100 µs to increase the size of the PSPs back to the control level. A 2nd pairing paradigm was the applied but it did not evoke potentiation of the PSPs in the presence of lowered [Ca2+]o. The control stimulation parameters (duration: 50 µs) and the control ACSF solution with normal calcium levels (2.0 mM) were returned at the time point indicated by the 2nd arrow. The PSP recovered from the effect of the low [Ca2+]o. Then the pairing paradigm was repeated for a 3rd time in the control solution, successfully leading to enhanced PSP (+27% increase) again.
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Role of endogenous nitric oxide production
It has been shown that calcium influx from NMDA receptor activation can activate type I NOS, resulting in nitric oxide (NO) synthesis (Garthwaite et al. 1988
). NMDA receptor-mediated NO production also promotes release of glutamate (Montague et al. 1994
) from presynaptic terminals in the cortex. NO production also can modulate synaptic potentiation in the mature visual cortex (Harsanyi and Friedlander 1997
) and in the hippocampus (Schuman and Madison 1991
, 1994
; but see Williams et al. 1993
). Interestingly, the pairing-induced transient synaptic potentiation in neonatal cortical slices is inducible without activation of NMDA receptors (Fig. 5). Therefore we evaluated whether blockade of endogenous cortical NO production concordantly does not modulate this synaptic plasticity in the neonate. L-nitro-arginine (LNA) (100 µM) was bath applied for several hours (>3 h) to sufficiently distribute the blocker compound in the entire slice preparation. Superfusion of LNA did not alter the likelihood of potentiation (81% = 13 of 16 vs. 75% = 40 of 53 in ACSF,
2 = 0.23, P = 0.631; Fig. 6B). The failure of prior long-term inhibition of NO production to block transient synaptic potentiation induction is illustrated in Fig. 6A, in which the repeated pairing protocols reliably evoke potentiation of the PSPs. Results are summarized in Fig. 6B. Note that in the cortex of young animals, the magnitude of potentiation likewise was not affected by LNA (+38 ± 7% vs. +40 ± 3% in control ACSF). These results, in contrast to those in the mature cortex (Fig. 7 in Harsanyi and Friedlander 1997
), suggest that neither NMDA receptors nor endogenous NO production play an essential or modulatory role in transient synaptic potentiation in the young visual cortex.
Dependence on postsynaptic calcium
The level of intracellular calcium concentration within the postsynaptic terminal is a critical factor in various forms of synaptic plasticity including induction of hippocampal (Lynch et al. 1983
; Malenka et al. 1988
) and cortical (Baranyi and Szente 1987
; Kimura et al. 1990
) long-term potentiation (LTP) and long-term depression (LTD). Moreover, our low-frequency pairing protocol in the mature visual cortex also requires a postsynaptic intracellular calcium signal in addition to NMDA receptor activation (Harsanyi and Friedlander 1997
). In light of our observation that this type of synaptic plasticity is not dependent on NMDA receptor activation or NO production in the immature cortex, we evaluated the role of intracellular postsynaptic calcium in the induction of synaptic potentiation in young animals. Experiments were performed with the use of intracellular application of the calcium chelator BAPTA, or by reversibly lowering the extracellular calcium concentration. Similar to results in mature animals, when intracellular calcium was chelated in the neonate (BAPTA-containing micropipettes) the pairing protocol never (n = 0 of 11) induced synaptic potentiation. Pairing protocols in the presence of BAPTA either resulted in no change (n = 8 of 11) in synaptic strength (Fig. 7A: 1st postpairing period), or in significant sustained synaptic depression (n = 3 of 11; average reduction in PSP amplitude:
25 ± 2%) (Fig. 7A: 2nd postpairing period) of synaptic strength. Because of the cases of synaptic depression, the average change in PSP size after the pairing protocols in the presence of the intracellular calcium chelator was a decrease of
7 ± 4% (Fig. 7B).
Lowering extracellular calcium concentration from the control level of 2.0 to 1.0 mM also prevented the occurrence of transient potentiation (n = 2 of 2) in neonatal neurons. One of these experiments is illustrated in Fig. 7C. The first pairing protocol was carried out during superfusion of control ACSF. Note that potentiation of the PSPs was induced initially and that subsequent reduction of extracellular calcium concentration decreased the size of the PSP, probably largely due to a reduction in presynaptic neurotransmitter release. The strength of the afferent stimulation was then increased (Fig. 7C, 1st arrow) to obtain a PSP size close to the control level. The subsequent pairing protocol did not evoke potentiation but resulted in a slight synaptic depression. When the superfusion was switched back to control ACSF, stimulus strength was also reset to the original level (Fig. 7B, 2nd arrow). After full recovery of the PSP size in the control solution, a subsequent pairing protocol successfully generated synaptic potentiation. In addition, intracellular application of the calcium store release inhibitor ryanodine (50 µM), in the recording microelectrode, consistently blocked the induction of transient synaptic potentiation. Ryanodine at this concentration level has been suggested to have an inhibitory effect on calcium-induced calcium release (Barish 1991
). Pairing protocols conducted in the presence of intracellular ryanodine did not lead to potentiation (n = 0 of 4), either causing synaptic depression(n = 1 of 4; Fig. 8A) or resulting in no change in the PSPs(n = 3 of 4 experiments; Fig. 8B). These results are consistent with a critical role for postsynaptic intracellular calcium, from sources other than a transmembrane flux through NMDA channels, in the induction of pairing-induced synaptic potentiation in the young visual cortex.

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| FIG. 8.
Intracellular ryanodine prevents the synaptic potentiation. A: recordings were made with microelectrodes containing ryanodine (50 µM; see drawing). In this PND 18 neuron, the pairing protocol (+2.0 nA) induced a significant synaptic depression ( 40%) of the PSPs in the presence of intracellular ryanodine. B: 2 pairing protocols (+1.8- and +2.4-nA pulses, respectively) were conducted on the neuron (PND 12), and no change in the synaptic response was recorded.
|
|
 |
DISCUSSION |
Transient synaptic potentiation in cortical neurons of young animals
A number of properties of this type of synaptic potentiation in the neonate are similar to those in the mature animal. In the neonate, the modification in synaptic efficiency occurs at excitatory synapses that directly impinge on the recorded neuron (Fig. 4), it requires a postsynaptic intracellular calcium signal (Fig. 7), and it does not require generation of action potentials (n = 5 of 5, not shown) in the postsynaptic cell during the pairing procedure. However, there is a quantitative difference in that transient potentiation in young animals is more readily induced (Fig. 2A), more robust (Fig. 2B), and longer lasting (Figs. 1, B and C, and 2C) than in the adult. There are other examples of such developmental regulation in the likelihood and efficacy of induction of synaptic potentiation (Abraham and Bear 1996
; Bolshakov and Siegelbaum 1995
; Harris and Teyler 1984
; Kato et al. 1991
; Kirkwood et al. 1995
; Perkins and Teyler 1988
). Indeed, in visual cortex, the ability to induce conventional LTP in supragranular layers from conditioning stimulation applied to the white matter is greatest in young rats (Kato et al. 1991
; Kirkwood et al. 1995
) and kittens (Komatsu and Iwakiri 1992
; Komatsu et al. 1981
, 1988
). Although transient potentiation is more readily induced and robust in the neonatal cortex than the adult cortex (Fig. 2), it is still a transient phenomenon, leading to significantly enhanced excitatory PSPs that persist from 5 to 140 min (overall mean 27 ± 3 min, mean ± SE).
NMDA receptor/NO-independent pathway for synaptic plasticity in the young neocortex
The most striking difference in transient synaptic potentiation observed in our experiments over the course of development is with respect to the induction mechanism. We showed in a previous study (Harsanyi and Friedlander 1997
) that NMDA receptor activation is necessary to induce the potentiation in the cortex of older animals. In contrast to the mature animals, transient potentiation occurs reliably in neonatal cortex in the presence of 50 µM APV (Fig. 5). Moreover, this level of APV is sufficient to block the NMDA receptor component of the PSP that is present (Fig. 5C) in layer II/III neurons. Our results of an NMDA receptor-independent synaptic potentiation in visual cortex layer III are consistent with other reports (Aroniadou and Teyler 1991
; Komatsu et al. 1991
). Similarly, Bear et al. (1992)
found that although blockade of NMDA receptors reduced the average magnitude and probability of synaptic potentiation, 25% of slices from kitten visual cortex still showed layer III LTP in the presence of 100 µM D,L-APV.
In our experiments, although APV did not block the induction of potentiation in neonates, it did slightly reduce the average magnitude of the initial potentiation (Fig. 5E). Thus the difference in the complete reliance of potentiation induction on NMDA receptors in older cortex versus a partial contribution in younger cortex implies that a redundant mechanism other than activation of conventional NMDA receptors is also at work in the neonate.
It is important to note that although neonatal transient synaptic potentiation has a strong NMDA receptor-independent component, it is still dependent on a rise in postsynaptic intracellular calcium (Fig. 7). This is in agreement with findings of Komatsu and Iwakiri (1992)
. The NMDA receptor-independent component of transient synaptic potentiation in neonatal guinea pig cortex may be mediated by voltage-gated calcium channels (VGCCs), as has been suggested for older rats (Aroniadou and Teyler 1992
; Aroniadou et al. 1993
). Consistent with a possible role for VGCCs, Kullman et al. (1992) reported that long (3 s) postsynaptic depolarizing pulses are sufficient to trigger transient synaptic potentiation in hippocampus. However, because our paradigm requires a temporal conjunction of synaptic activity and postsynaptic depolarization in the adults and neonates for potentiation induction, this implies that activation of postsynaptic VGCCs alone is not sufficient to trigger synaptic modification, and another mechanism must be responsible for the induction of transient synaptic plasticity.
It is possible that another form of NMDA receptor with a different pharmacological profile, that is APV insensitive, is expressed in the neonate (Burgard and Hablitz 1994
; Kato 1993
; Kato and Yoshimura 1993
; Monyer et al. 1994
; Zukin and Bennett 1995
). Another possibility is that
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors lacking a glutamate receptor 2 subunit (GluR2) and thus having a higher calcium permeability are more highly expressed in the neonate (Bochet et al. 1994
; Hollman et al. 1991
). However, they would also have to display a voltage dependence similar to that of NMDA receptors to act as coincidence detectors. Indeed, an additional postsynaptic coincidence detector has also been suggested for conventional hippocampal LTP in young animals (Kullman et al. 1992). Another possible contributor to the NMDA receptor-independent synaptic potentiation induction in the neonate is calcium-induced calcium release from postsynaptic intracellular stores (Fig. 8). Regardless of the source(s) of additional calcium (VGCCs, metabotropic glutamate receptors, or other messengers such as cyclic adenosine diphosphate ribose or cADPr) (Hua et al. 1994
; White et al. 1993
), the enhanced calcium signal would then lead to activation of appropriate post- and/or presynaptic modification of synaptic efficacy (Fig. 9).
The NMDA receptor-independent transient potentiation in the neonatal cortex is not affected by endogenous cortical NO production (Fig. 6). There is an interesting biochemical parallel to these pharmacological data. The ability of NMDA receptor activation to lead to facilitated glutamate release in a guinea pig cortical synaptosome preparation is also developmentally regulated (Friedlander et al. 1994
). This process is robust in the visual cortex of guinea pigs >3 postnatal weeks old and is dependent on the ability of NMDA receptor activation to produce NO (Montague et al. 1994
). However, in guinea pigs younger than PND 15, NMDA receptor activation does not enhance glutamate release (Friedlander et al. 1994
). NMDA receptors are expressed and active in the neonatal cortex (Fig. 5C), and the synaptosomes are capable of glutamate release in response to other types of stimulation. Thus the immaturity must either be in the effective linking of NMDA receptors to NOS activation, consistent with a recent report on the developmentally regulated NOS activity in the guinea pig cortex (Brien et al. 1995
), and/or the molecular cascades downstream from NO production that facilitate neurotransmitter release.
Our data show that transient synaptic potentiation induced by the pairing protocol in the neonatal visual cortex is more likely to occur and its magnitude is greater than in the adult. Although the potentiation is more persistent in the neonate, it is still transient in nature. As to the possible physiological significance of this phenomenon, transient synaptic potentiation may provide a mechanism to modify the functional connectivity in the primary visual cortex during early postnatal life, just as in the mature animal (Harsanyi and Friedlander 1997
). Moreover, transient potentiation could signify the earliest stages of visual cortex developmental plasticity, triggering events that can lead to anatomic remodeling of cortical microcircuits (Antonini and Stryker 1993
; Friedlander and Martin 1989
; Friedlander et al. 1991
; Reh and Constantine-Paton 1985
; Shatz and Stryker 1988
) and the fine tuning of feedforward-mediated receptive field properties (Singer 1995
).
 |
ACKNOWLEDGEMENTS |
We thank Drs. John Hablitz, Robin Lester, and Serena Dudek for reading drafts of the manuscript and providing insightful suggestions, and J. Neville and D. Burton for secretarial assistance. K. Ramer wrote the customized software used for data acquisition.
This work was supported by National Institutes of Health Grants EY-05116, HD-32901, and HFSP RG-69193 and training grant T32 EY07033-18, and by the Helen Keller Eye Research Foundation.
 |
FOOTNOTES |
Address for reprint requests: M. J. Friedlander, Department of Neurobiology, 516 Civilian International Research Bldg., University of Alabama at Birmingham, Birmingham, AL 35294.
Received 16 July 1996; accepted in final form 26 November 1996.
 |
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