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. 2014 Feb;24(2):521-31.
doi: 10.1093/cercor/bhs334. Epub 2012 Oct 31.

Pansynaptic enlargement at adult cortical connections strengthened by experience

Claire E J Cheetham  1 , Samuel J Barnes, Giorgia Albieri, Graham W Knott, Gerald T Finnerty
Affiliations

Pansynaptic enlargement at adult cortical connections strengthened by experience

Claire E J Cheetham et al. Cereb Cortex. 2014 Feb.

Abstract

Behavioral experience alters the strength of neuronal connections in adult neocortex. These changes in synaptic strength are thought to be central to experience-dependent plasticity, learning, and memory. However, it is not known how changes in synaptic transmission between neurons become persistent, thereby enabling the storage of previous experience. A long-standing hypothesis is that altered synaptic strength is maintained by structural modifications to synapses. However, the extent of synaptic modifications and the changes in neurotransmission that the modifications support remain unclear. To address these questions, we recorded from pairs of synaptically connected layer 2/3 pyramidal neurons in the barrel cortex and imaged their contacts with high-resolution confocal microscopy after altering sensory experience by whisker trimming. Excitatory connections strengthened by experience exhibited larger axonal varicosities, dendritic spines, and interposed contact zones. Electron microscopy showed that contact zone size was strongly correlated with postsynaptic density area. Therefore, our findings indicate that whole synapses are larger at strengthened connections. Synaptic transmission was both stronger and more reliable following experience-dependent synapse enlargement. Hence, sensory experience modified both presynaptic and postsynaptic function. Our findings suggest that the enlargement of synaptic contacts is an integral part of long-lasting strengthening of cortical connections and, hence, of information storage in the neocortex.

Keywords: barrel cortex; confocal microscopy; electrophysiology; experience-dependent plasticity; structural plasticity.

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Figures

Figure 1.
Figure 1.
Imaging putative synapses between L2/3 pyramidal neurons. (A) Whisker trimming paradigm. An A–C row trim protocol is shown. (B) Brain slice showing neurons filled with AF488 (green; presynaptic) and AF568 (red; postsynaptic) in the D (spared) barrel column. Scale bar: 250 μm. (C) Train of presynaptic action potentials and postsynaptic excitatory postsynaptic potentials (EPSPs) (average of 50 trials) recorded from the neurons shown in B. Scale bars: 40 mV, 0.2 mV; 50 ms. (D) A montage of maximum intensity projections of confocal z-stacks through the filled neurons shown in B. Dashed line indicates the pia. Scale bar: 20 μm. (E) Single optical sections showing a presynaptic axonal varicosity (i; green), a postsynaptic dendritic spine (ii; orange), and the interposed contact zone (iii; magenta arrowhead). Scale bar: 1 μm.
Figure 2.
Figure 2.
Axonal varicosities and dendritic spines are larger in spared cortex. (A) Left panels show maximum intensity projections of segments of axon in spared cortex. Arrowheads indicate en passant (i) and terminaux (ii) varicosities that form putative synapses. Right panels show single optical sections through the putative synapses formed by these varicosities. Scale bars: 1 μm. (B) Empirical distribution functions for the volumes of putative synapse-forming varicosities in control (n = 40 varicosities from 13 connections) and spared (n = 44 varicosities from 12 connections) cortex. *P = 0.020, Andersen–Darling test. (C) Volumes of en passant and terminaux varicosities forming putative synapses. Note: log scale, *P = 0.010, t-test. (D) Left panels show single optical sections through segments of dendrite from spared cortex. Arrowheads indicate mushroom (i), stubby (ii), and thin (iii) spines that form putative synapses. Right panels show single optical sections through the putative synapses formed by these spines. Scale bars: 1 μm. (E) Empirical distribution functions for the volumes of putative synapse-forming dendritic spines in control (n = 27 spines from 13 connections) and spared (n = 25 spines from 12 connections) cortex. *P = 0.038, Kolmogorov–Smirnov test. (F) Volumes of mushroom and stubby spines forming putative synapses. Note: log scale, **P = 0.007 for spines in control versus spared cortex, 2-way ANOVA.
Figure 3.
Figure 3.
Contact zones are larger in spared cortex. (A) Example of a putative local excitatory synapse from control cortex. The contact zone (white) has been projected onto 3 planes (left, XY; right, YZ; lower, XZ). Scale bar: 1 μm. (B) Empirical distribution functions for contact zone size in control (n = 40 putative synapses from 13 connections) and spared (n = 44 putative synapses from 12 connections) cortex. **P = 0.006, Kolmogorov–Smirnov test. (C) Relationship between contact zone size and varicosity volume for individual putative synapses. Voxels are ∼0.001 μm3. Lines represent generalized estimating equation fits: E(contact zone voxels) = 29.8 + 313(varicosity volume) + 23.8(SP) + 58.5(SHAFT) for putative synapses formed on dendritic spines (solid) and dendritic shafts (dashed). ***P < 0.001 for slope for all groups. (D) Relationship between contact zone size and spine volume for individual putative synapses. Lines represent generalized estimating equation fits: E(contact zone voxels) = 74.4 + 140(spine volume) + 125(SP × spine volume); ***P< 0.001 for the slope for both groups; ††P = 0.002 for control versus spared.
Figure 4.
Figure 4.
Contact zone size scales with synapse size in spared cortex. (A) Three consecutive EM sections through a synaptic bouton (b) synapsing (arrowhead) with a dendritic spine (s). Scale bar, 0.5 μm. (B) 3D reconstruction of the bouton and spine shown in A made from serial images. (C) Relationship between PSD area and synaptic contact zone area for excitatory synapses (n = 34) in L2/3 of spared cortex. Line represents the fit from the generalized linear model: PSD area = 0.009 + 0.53(contact zone area); explained deviance 89%, ***P < 0.001 for all synapses.
Figure 5.
Figure 5.
Excitatory connections in spared cortex are stronger and more reliable. (A) Example recordings of: (i) presynaptic action potential and postsynaptic failure; (ii) presynaptic action potential and maximum evoked uEPSPs in control (blue) and spared (orange) cortex (single traces). Scale bars: 40 mV, 0.5 mV; 10 ms. (B) Scatterplot of probability of failure. *P = 0.020, Mann–Whitney test. (C) Scatterplot of maximum evoked uEPSP amplitude. *P = 0.032, t-test. (D) Relationship between mean contact zone size and probability of failure. Curve represents the power fit to data, y = (1–0.0017x)3.65. (E) Relationship between mean contact zone size and maximum evoked uEPSP amplitude per synapse. Line represents linear regression fit to all data points; Maximum evoked uEPSP amplitude = 0.0629 + 0.0012(mean contact zone size). n = 13 control and 10 spared connections. (F) Schematic showing that naïve synapses (i; active zone, red; postsynaptic density, blue; contact zone, cyan) become functionally stronger and structurally larger in spared cortex (ii).
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