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Science 4 January 2008:
Vol. 319. no. 5859, pp. 101 - 104
DOI: 10.1126/science.1143808
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Reports

Ongoing in Vivo Experience Triggers Synaptic Metaplasticity in the Neocortex

Roger L. Clem1, Tansu Celikel2* and Alison L. Barth1{dagger}

1 Department of Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
2 Department of Cell Physiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.


Figure 1 Fig. 1. LTP and SWE-induced synaptic strengthening require NMDARs. (A) Pairing (0 mV, 2 Hz, 360 pulses) induces LTP at layer 4-2/3 synapses from control undeprived mice (white circles) that is abolished in APV-treated cells (black circles). t, time. *P < 0.01. (B) Coronal slice of the barrel cortex under brightfield illumination. (C) Fluorescence illumination of (B) showing fosGFP expression in the spared barrel column (arrow). Scale bar, 500 µm. (D) Electrode positions. (E) Experimental groups for (F) to (J): control, whisker intact; SWE, 24 hours of SWE; SWE + CPP, 24 hours of SWE with recurrent CPP treatment. (F) Representative EPSCs at membrane holding potential (Vh) = –70 mV and +40 mV, scaled to +40 mV. Scale bars, 25 pA, 20 pA, and 25 pA x 20 ms, respectively. (G) Mean A:N ratio for all groups. *P < 0.001. (H) Group-averaged quantal Sr2+-mEPSCs. Scale bar, 5 pA x 5 ms. (I) Mean Sr2+-mEPSC amplitude. *P < 0.001. (J) Cumulative histogram of Sr2+-mEPSC amplitude for all groups. *P < 0.001. [View Larger Version of this Image (61K GIF file)]
 

Figure 2 Fig. 2. SWE occludes pairing-induced LTP in vitro. (A and D) Electrode positions for recording in deprived (A) or spared (D) columns. (B and C) Representative experiments showing pairing-induced LTP in a deprived column (B) that is abolished in APV-treated cells (C). Inset in (B), (C), and (E) shows averaged EPSC before pairing (gray) and 30 min after pairing (black). Scale bar in (B), 10 pA x 10 ms; in (C), 20 pA x 10 ms. (E) Representative experiment showing that LTP is not elicited in the spared column. Scale bar, 30 pA x 10 ms. (F) Summary of LTP experiments at 4-2/3 synapses in spared (triangles), deprived (white squares), and deprived + APV (black squares) columns. P < 0.01. [View Larger Version of this Image (34K GIF file)]
 

Figure 3 Fig. 3. NMDAR block reveals mGluR- and Ca2+-dependent LTP at spared column synapses. (A) Electrode positions. (B to E) For pairing at 4-2/3 synapses within the spared column of slices from SWE animals, representative experiments for (B) APV, (C) APV + BAPTA, (D) APV + JsTX or PhTX (data pooled), and (E) APV + MCPG are shown. Scale bars in (B), 40 pA x 10 ms; in (C), 30 pA x 10 ms; in (D), 60 pA x 10 ms; in (E), 20 pA x 10 ms. (F) Summary of pairing-induced plasticity experiments. APV-only (white squares), APV + BAPTA (black squares), APV + PhTX or JsTX (black circles), and APV + MCPG (white triangles). *P < 0.01. [View Larger Version of this Image (33K GIF file)]
 

Figure 4 Fig. 4. NMDARs and mGluRs oppositely regulate synaptic strength and behavioral plasticity in vivo after SWE initiation. (A) Experimental timeline for joint SWE and in vivo drug delivery. CPP or AIDA was injected 18 hours after SWE onset. Slices were prepared 6 hours later. (B) Representative layer 4-2/3 EPSCs at Vh = –70 mV and +40 mV for each experimental group, scaled to peak current at +40 mV. Scale bars: control, 25 pA; control + CPP, 25 pA; control + AIDA, 40 pA; SWE spared, 20 pA; SWE spared + CPP, 30 pA; SWE spared + AIDA, 60 pA x 20 ms. (C) Mean A:N ratio for all groups. (D) Group-averaged Sr2+-mEPSCs. Scale bar, 5 pA x 10 ms. (E) Mean Sr2+-mEPSC amplitude. (F) Cumulative histogram of Sr2+-mEPSC amplitude. *P <0.001 versus control. (G) Experimental setup for associative tactile conditioning. Whisker deflections [CS, 100 ms (up) and 400 ms (down) at 2 Hz for 30 s] were paired with air-puff stimuli (US, 3 bars, 5 s overlapping with last 5 s of CS), and animal mobility was quantified from video recordings during conditioning by custom-written software. As animals learned to associate the whisker deflections with the air-puff stimuli, they tended to increase their mobility to avoid the upcoming US. (H) Fraction of time spent immobile in test chamber immediately before CS onset did not differ between test groups, indicating that whisker deprivation or drug treatment did not influence mobility. (I) Animal mobility normalized to movement before CS. *P < 0.05 versus control. (J) Cumulative distribution of mobility over all trials shows that SWE mice learned faster than controls and that SWE + CPP mice learned faster than SWE and control animals. SWE + AIDA animals failed to acquire the task, with equal mobility responses for each training trial (linear fit for cumulative mobility). *P < 0.01 for all pairwise comparisons across groups. [View Larger Version of this Image (48K GIF file)]
 

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