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J Neurophysiol 91: 1097-1101, 2004; doi:10.1152/jn.00443.2003
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Silent Synapses in the Immature Visual Cortex: Layer-Specific Developmental Regulation

Simon Rumpel, Gunnar Kattenstroth and Kurt Gottmann

Department of Cell Physiology, Ruhr-University Bochum, D-44780 Bochum, Germany

Submitted 8 May 2003; accepted in final form 20 October 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Central glutamatergic synapses are thought to initially form as immature, so-called silent synapses showing exclusively N-methyl-D-aspartate receptor-mediated synaptic transmission. Postsynaptic insertion of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors during further development leads to a conversion into functional, mature synapses. Here, we tested the hypothesis that, according to the "inside first–outside last" pattern of neocortical layer formation and synaptogenesis, pyramidal cells in the superficial layers might show a higher fraction of silent synapses compared with pyramidal cells in the deep layers. We performed an electrophysiological analysis of glutamatergic synapses in acute rat visual cortex slices during postnatal development. In layer VI pyramidal neurons the incidence of silent synapses was high during the first postnatal week and strongly declined during further development. Surprisingly, in superficial cortical plate pyramidal neurons (immature layers II/III), the fraction of silent synapses was initially very low and increased up to the second postnatal week. Thereafter, a similar decline as found in layer VI pyramidal neurons was observed. Thus the developmental regulation of silent synapses was clearly different in pyramidal neurons from different neocortical layers. The almost complete absence of silent synapses at early stages in layer II/III pyramidal neurons indicates that an initially formed subset of synapses is constitutively functional. This might be important to enable spontaneous activity and latter activity-dependent maturation of synapses.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
The formation of cortical layers occurs in an inside-out pattern: neurons of the deep layers are generated first and stop migratory activity earlier than neurons destined for the superficial layers (Rakic 1982Go; Takahashi et al. 1999Go). Synapse formation also follows an inside-out gradient: in rats synaptogenesis occurs pimarily in deep layers up to postnatal day 6 (P6), whereas after P8 most neocortical synapses are formed in the upper layers (Blue and Parnavelas 1983Go; Zielinski and Hendrickson 1992Go).

In this study, we examined the hypothesis that the functional maturation of glutamatergic synapses similarly follows the general inside-out developmental gradient of the neocortex. We focused on the developmental regulation of silent glutamatergic synapses, which show exclusively N-methyl-D-aspartate (NMDA) receptor–mediated transmission. It has been suggested that this type of silent synapse lacks functional {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Isaac et al. 1995Go; Liao et al. 1995Go; Malinow et al. 2000Go; Petralia et al. 1999Go; Rumpel et al. 1998Go). In principle, a low synaptic concentration of glutamate, which is not sufficient to activate AMPA receptors, could also explain silent synapses showing exclusively NMDA receptor–mediated responses (Asztely et al. 1997Go; Choi et al. 2000Go; Renger et al. 2001Go). However, we previously did not find any evidence for lower glutamate concentrations at neocortical silent synapses (Rumpel et al. 1998Go).

Intriguingly, silent synapses can be rapidly converted to functional synapses with AMPA receptors in an activity-dependent way and in all brain regions looked at thus far, the incidence of silent synapses has been described to strongly decline during postnatal development (Durand et al. 1996Go; Isaac et al. 1997Go; Plitzko et al. 2001Go; Rumpel et al. 1998Go; Wu et al. 1996Go; Zhu et al. 2000Go). Therefore it has been suggested that silent synapses represent immature glutamatergic synapses.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Wistar rat pups were killed by decapitation prior to isolating the brain. Coronal slices (300–500 µm thick) of the visual cortex were cut with a vibratome. Slices were incubated in artificial cerebrospinal fluid (ACSF) containing (in mM) 125 NaCl, 3 KCl, 1.25 NaH2PO4, 25 NaHCO3, 20 glucose, 2.5 CaCl2, and 1.5 MgCl2, saturated with 95% O2-5% CO2, pH 7.3 and allowed to recover at room temperature for >=1 h. All recordings were made in a submerged slice chamber at 28–30°C. The slice chamber was continuously perfused with ACSF containing picrotoxin (100 µM) to block GABAA receptors. Whole cell patch-clamp recordings were obtained from visually identified pyramidal neurons in different cortical layers using infrared videomicroscopy. Patch pipettes (resistance: 7–10 M{Omega}) were filled with an intracellular solution containing (in mM) 135 CsCl, 20 TEA-Cl, 2 MgCl2, 10 HEPES, 10 EGTA, pH 7.3. To study rectification properties of AMPA receptors, 100 µM spermine was added. Postsynaptic currents (PSC) were evoked with a bipolar tungsten stimulation electrode located 100–400 µm lateral to the soma of the recorded cell. Stimulation frequency was 0.2 Hz and stimulation strength was adjusted until failures were clearly observed at +40 mV holding potential. Recordings were made with a HEKA (Lambrecht/Pfalz, Germany) EPC-7 patch-clamp amplifier, filtered at 3 kHz, and sampled at 20 kHz (-80 mV holding) or 2 kHz (+40 mV holding) with a TL-1 interface using pClamp software (Axon Instruments, Union City, NJ).

AMPA receptor–mediated miniature excitatory postsynaptic currents (mEPSCs) were evoked by local pressure application (2–3 M{Omega} pipette, 150 mmHg) of hypertonic solution (500 mM sucrose added) to the proximal part of the apical dendrite for 1 s and were recorded in the presence of 0.5 µM TTX, 100 µM picrotoxin, and 25 µM D-2-amino-5-phophonopentanoic acid (D-AP5). Data analysis (detection of failures) was performed as described (Rumpel et al. 1998Go). Statistical comparison of mean values was done using a two-tailed Student's t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
To study the presence of silent synapses at P3–4 qualitatively, we performed whole cell patch-clamp recordings of spontaneous, pharmacologically isolated glutamate receptor–mediated postsynaptic currents (sPSCs) from visually identified pyramidal neurons in rat visual cortex slices (Rumpel et al. 1998Go). AMPA receptor–mediated sPSCs were recorded at -80 mV and mixed, AMPA and NMDA receptor–mediated sPSCs at +40 mV holding potential (Fig. 1A). In these experiments the presence of silent synapses was indicated by a higher sPSC frequency at +40 mV compared with that at -80 mV, because silent synapses contribute only NMDA receptor–mediated PSCs. For statistical comparison, we calculated the ratio of sPSC frequencies at -80 mV and at +40 mV holding potential for each cell. In pyramidal neurons in layer VI the prominent presence of silent synapses was indicated by a sPSC frequency ratio of 0.43 ± 0.09 (n = 13; Fig. 1B) in the presence of Mg2+. Intriguingly, in pyramidal neurons in the more superficial cortical plate (immature layers II/III) the sPSC frequency ratio was significantly (P < 0.01) higher (0.96 ± 0.18; n = 12) compared with layer VI pyramidal neurons and close to 1, suggesting that the vast majority of glutamatergic synapses was fully functional.



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  		FIG. 1. Spontaneous glutamate receptor–mediated postsynaptic currents (PSCs) in neocortical pyramidal neurons at postnatal day (P)3–4. A: mixed N-methyl-D-aspartate (NMDA) and {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated PSCs were recorded at +40 mV holding potential, pure AMPA receptor-mediated PSCs at -80 mV holding potential in pyramidal neurons in layer VI and in the superficial cortical plate (immature layers II/III), respectively. *AMPA sPSCs. B: mean ratios of spontaneous PSC (sPSC) frequency at -80 mV to that at +40 mV. The presence of silent synapses is indicated only in layer VI pyramidal neurons. *Significant difference. Error bars represent SE. n is indicated above bars.

 
To estimate the fraction of silent synapses quantitatively and to study their developmental regulation, whole cell patch-clamp recordings were obtained from pyramidal neurons on P2–23. Pharmacologically isolated glutamatergic PSCs were evoked by intracortical minimal stimulation (100–400 µm lateral to the soma) and were recorded at +40 and -80 mV holding potential (Fig. 2A). Silent synapses cannot contribute to synaptic transmission at strongly negative potentials due to the block of NMDA receptors by Mg2+. Therefore the presence of silent synapses is indicated by a higher failure rate at hyperpolarized compared with depolarized membrane potentials (or equivalently by a higher success rate at depolarized potentials). For estimation of the fraction of silent synapses, the ratio of success rates at -80 to +40 mV was calculated for each cell individually. Success rate analysis of evoked PSCs recorded from layer VI pyramidal neurons revealed a strong, significant (P < 0.001) developmental decrease in the fraction of silent synapses between P2–4 and P19–23 (Fig. 2B). In contrast, the vast majority of glutamatergic synapses in the more superficial cortical plate (immature layers II/III) were found to be functional at P2–4 and the fraction of silent synapses significantly (P < 0.001) increased up to P11–14. Thereafter the fraction of silent synapses significantly (P < 0.001) decreased up to P19–23 similar to layer VI pyramidal neurons.



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  		FIG. 2. Developmental regulation of silent glutamatergic synapses is different in pyramidal neurons in layers II/III and in layer VI, respectively. A: typical consecutive recordings of glutamate receptor–mediated PSCs and failures evoked by minimal stimulation at P2–4. *Failures. Neocortical layers and holding potentials are indicated. B: success rates at -80 mV holding potential were normalized to success rates at +40 mV holding potential at the indicated developmental stages. A high success rate ratio correlates to a low fraction of silent synapses and vice versa. Error bars represent SE. n is indicated at symbols.

 
The analysis of the kinetics of AMPA PSCs evoked by minimal stimulation and recorded at -80mV revealed a slight increase in the mean 10–90% rise time (layers II/III: 1.0 ± 0.1 ms at P2–4; 1.6 ± 0.2 ms at P11–14; 2.4 ± 0.4 ms at P19–23; layer VI: 1.4 ± 0.2 ms at P2–4; 1.4 ± 0.2 ms at P11–14; 2.0 ± 0.1 ms at P19–23) and in the mean decay time constant (layers II/III: 3.0 ± 0.2 ms at P2–4; 3.7 ± 0.4 ms at P11–14; 11.4 ± 4.5 ms at P19–23; layer VI: 3.6 ± 0.5 ms at P2–4; 3.5 ± 1.7 ms at P11–14; 7.5 ± 2.4 ms at P19–23) of AMPA PSCs during postnatal development. This observation is in line with an increased density of functional synapses at P19–23. The kinetics of PSCs at +40 mV were dominated by the NMDA receptor–mediated component as indicated by much larger mean 10–90% rise times (layer II/III: 9.8 ± 0.5 ms at P2–4; 11.3 ± 0.6 ms at P11–14; 9.8 ± 1.1 ms at P19–23; layer VI: 11.3 ± 1.0 ms at P2–4; 9.0 ± 0.5 ms at P11–14; 12.6 ± 2.1 ms at P19–23). The mean decay kinetics at +40 mV reflected the well-described developmental change in the expression of NR2 subunits (Carmignoto and Vicini 1992Go; Hoffmann et al. 2000Go) with an additional, rapidly decaying current component appearing at P11–14 (P2–4, monoexponential decay: 296 ± 15 ms in layers II/III and 265 ± 11 ms in layer VI; P11–14, biexponential decay: 62 ± 26 and 323 ± 136 ms in layers II/III and 65 ± 8 and 289 ± 26 ms in layer VI).

To corroborate the unexpected finding that the incidence of silent synapses transiently increased in layers II/III, we studied the number of AMPA receptor–mediated mEPSCs that were evoked by pressure application of hypertonic solution (500 mM sucrose for 1 s) to a defined (60 µm), proximal part of the apical dendrite (Fig. 3A). At P3–4 a mean number of 13 ± 3 mPSCs (n = 6 cells) and at P12–14 a mean number of 53 ± 10 (n = 10; P < 0.01) mPSCs was evoked by sucrose stimulation (Fig. 3, B and C). Mean mPSC amplitudes also significantly (P < 0.001) increased (P3–4: 12.4 ± 1.3 pA; P12–14: 20.6 ± 0.9 pA). This fourfold increase in the frequency of sucrose-evoked mEPSCs corresponds to a more than 10-fold increase in the density of asymmetric synapses in layers II/III (Blue and Parnavelas 1983Go), thus supporting an increase in the fraction of silent synapses. In summary, the quantitative analysis of the incidence of silent synapses revealed specific developmental patterns for pyramidal neurons from different layers. In particular, at early postnatal stages a dramatic difference was observed with almost no silent synapses found in pyramidal neurons from immature layers II/III.



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  		FIG. 3. Developmental increase in the frequency of AMPA receptor–mediated miniature evoked postsynaptic currents (mEPSCs) evoked by local sucrose application in layers II/III pyramidal neurons. A: Lucifer yellow-filled pyramidal neuron prior to (a) and during sucrose (with addition of FITC) application (b). Patch pipette (left) and application pipette (right) are indicated by dotted lines. B: *typical sucrose-evoked mEPSCs recorded at P3–4, P12–14, and P12–14 in the presence of 10 µM 6,7-dinitroquinoxaline-2,3-dione. Holding potential: -80 mV. Sucrose (500 mM) application is indicated by black bar. C: quantitative comparison of the mean number of mEPSCs evoked by sucrose application. Error bars represent SE. n is indicated above bars.

 
Next, we characterized the properties of AMPA receptors contributing to glutamate receptor–mediated PSCs. Evoked PSCs recorded at -80 mV holding potential were completely blocked at P3–4 as well as at P11–12 by the specific AMPA receptor antagonist SYM 2206 (100 µM) (Li et al. 1999Go) in both layers II/III and layer VI pyramidal neurons (n = 19; Fig. 4A). This indicates that, even in superficial cortical plate (immature layers II/III) pyramidal neurons at P3–4, PSCs are mediated by AMPA receptors. Analysis of the current–voltage relationship of evoked AMPA PSCs revealed strong rectification at positive potentials at P3–4, whereas at P12–14 linear current–voltage relationships were observed (Fig. 4, B and C). These rectification properties suggest that most synaptic AMPA receptors at P3–4 lack GluR2 subunits in both superficial cortical plate (immature layers II/III) pyramidal neurons and layer VI pyramidal neurons (Metin et al. 2000Go; Verdoorn et al. 1991Go; Zhu et al. 2000Go). During further postnatal development the appearance of GluR2 subunits was indicated by a clear change in rectification properties.



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  		FIG. 4. Properties of synaptic AMPA receptors in layers II/III pyramidal neurons. A: evoked PSCs at -80 mV holding potential were completely blocked by the specific AMPA receptor antagonist SYM2206 at P3–4 and at P11–12, respectively. Data shown are from layer II/III pyramidal neurons; similar observations were made in layer VI pyramidal neurons. B: membrane potential dependence of evoked AMPA PSCs in the presence of 25 µM D-AP5 at P3–4 and at P11–12, respectively. Ten individual PSCs were averaged. Insets: current–voltage relationships. Data shown are from layer II/III pyramidal neurons; similar observations were made in layer VI pyramidal neurons. Scale bars in A and B = 20 pA and 5 ms. C: developmental changes in rectification properties of AMPA receptor–mediated PSCs in layers II/III and layer VI pyramidal neurons, respectively. *Significant differences. Error bars represent SE. n is indicated above bars.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
In summary, our major new finding is that the majority of glutamatergic synapses was functional at early stages of synapse formation in pyramidal neurons in the immature layers II/III and we see an increase in the fraction of silent synapses during the following days. There are several possible mechanistic models that can account for this surprising developmental profile. We would like to discuss two of them in more detail, which both are based on the standard model of AMPA receptor insertion via a NMDA receptor–dependent process. According to the first model, synapses that are already functional during early stages of synaptogenesis (Metin et al. 2000Go; Rohrbough and Spitzer 1999Go) might acquire AMPA receptors completely independent of activity. Neurotrophic factors such as insulin or neurotrophins might play a major role in activity-independent, constitutive synaptic appearance of AMPA receptors (Passafaro et al. 2001Go; Plitzko et al. 2001Go). During later stages of synaptogenesis, synapses are then formed as silent synapses that get eventually converted into functional synapses.

The second model assumes that glutamatergic synapses always acquire AMPA receptors in an activity-dependent manner (Malinow and Malenka 2002Go). However, during the first postnatal days AMPA receptors are very readily inserted into synapses. This would lead to a fast transition of silent synapses to functional synapses, ultimately resulting in a low fraction of silent synapses at a given point in time. The observed transient increase in the fraction of silent synapses in layers II/III during further development might reflect changes in the expression of AMPA receptor subunits. Increasing levels of AMPA receptor subunits that have different interaction partners and that are less readily incorporated into synapses might prolong the time before silent synapses finally become converted into functional synapses. This ultimately would lead to an increase in the fraction of silent synapses. Recent work has shown that incorporation of receptors is mediated via specific interaction of the cytoplasmic C-termini and postsynaptically localized proteins, with individual AMPA-receptor subunits having different interaction partners (Malinow and Malenka 2002Go). It has been shown in cultured hippocampal neurons that expression patterns of GluR4 and GluR1 subunits change during development and their synaptic incorporation is indeed differentially regulated (Esteban et al. 2003Go; Zhu et al. 2000Go). In both models the disappearance during later development is most likely due to a decrease in the formation of new silent synapses and to the activity-dependent conversion of silent synapses to functional ones.

It has to be emphasized that both models assume a constitutive incorporation of NMDA receptors at synapses. Therefore a third alternative might be based on an activity-dependent insertion of both AMPA and NMDA receptors during early synaptogenesis. A developmental, selective reduction in the activity dependence of NMDA receptor insertion could in principle also lead to an increase in NMDA receptor-only synapses. Moreover, the increase in silent synapses between P2–4 and P11–14 could also be caused by a loss of AMPA receptors during further maturation of early formed synapses. However, since the overall number of synapses as estimated by electron microscopy increases more than 10-fold in layers II/III (Blue and Parnavelas 1983Go), the contribution of the early formed synapses is minor at P11–14.

Regarding their physiological function, we hypothesize that early functional synapses in immature layers II/III might form an initial, crude scaffold that is crucial for the generation and spread of correlated network activity. This kind of network activity enables later activity-dependent maturation and refinement of synaptic circuits. In line with this hypothesis, early spontaneous network activity in ento/perirhinal cortex (Garaschuk et al. 2000Go) and the visual cortex (Rumpel and Gottmann, unpublished observations) has been shown pharmacologically to depend strongly on functional AMPA receptors and has been proposed to play a central role in the differentiation of the neocortical network.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Drs. J.T.R. Isaac and V. Le{beta}mann for comments on the manuscript and Dr. H. Hatt for continous support.

Present addresses: S. Rumpel, Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor NY, 11724. K. Gottmann is at the Max-Planck-Institute for Experimental Medicine, Dept Molecular Neurobiology, Hermann-Rein-Str. 3, 37075 Göttingen, Germany.

GRANTS

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 509 "Neurovision"/C1 and Graduiertenkolleg "KOGNET").


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: K. Gottmann, Department of Cell Physiology ND4, Ruhr-University Bochum, D-44780 Bochum, Germany (E-mail: kurt.gottmann{at}ruhr-uni-bochum.de).


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 DISCUSSION
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 REFERENCES
 
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