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. 2012 Feb;107(3):902-12.
doi: 10.1152/jn.00780.2011. Epub 2011 Nov 23.

Developmental regulation of the late phase of long-term potentiation (L-LTP) and metaplasticity in hippocampal area CA1 of the rat

Guan Cao  1 , Kristen M Harris
Affiliations

Developmental regulation of the late phase of long-term potentiation (L-LTP) and metaplasticity in hippocampal area CA1 of the rat

Guan Cao et al. J Neurophysiol. 2012 Feb.

Abstract

Long-term potentiation (LTP) is a form of synaptic plasticity thought to underlie memory; thus knowing its developmental profile is fundamental to understanding function. Like memory, LTP has multiple phases with distinct timing and mechanisms. The late phase of LTP (L-LTP), lasting longer than 3 h, is protein synthesis dependent and involves changes in the structure and content of dendritic spines, the major sites of excitatory synapses. In previous work, tetanic stimulation first produced L-LTP at postnatal day 15 (P15) in area CA1 of rat hippocampus. Here we used a more robust induction paradigm involving theta-burst stimulation (TBS) in acute slices and found the developmental onset of L-LTP to be 3 days earlier at P12. In contrast, at P8-11, TBS only reversed the synaptic depression that occurs from test-pulse stimulation in developing (P8-15) hippocampus. A second bout of TBS delivered 30-180 min later produced L-LTP at P10-11 but not at P8-9 and enhanced L-LTP at P12-15. Both the developmental onset and the enhanced L-LTP produced by repeated bouts of TBS were blocked by the N-methyl-d-aspartate receptor antagonist dl-2-amino-5-phosphonovaleric acid. Thus the developmental onset age is P12 for L-LTP induced by the more robust and perhaps more naturalistic TBS induction paradigm. Metaplasticity produced by repeated bouts of TBS is developmentally regulated, advancing the capacity for L-LTP from P12 to P10, but not to younger ages. Together these findings provide a new basis from which to investigate mechanisms that regulate the developmental onset of this important form of synaptic plasticity.

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Figures

Fig. 1.
Fig. 1.
Within-slice experiments. A: arrangement of stimulating (Stim. 1, 2) and recording (rec.) electrodes in the middle of stratum radiatum of hippocampal area CA1. DG, dentate gyrus. B–I: for all ages, the field excitatory postsynaptic potential (fEPSP) slope is expressed as a percentage of the average baseline response obtained for 20 min before delivery of theta-burst stimulation (TBS) at time 0 (green arrow) to 1 of the stimulating electrodes, alternating between locations across experiments at each age (see Fig. 2C for TBS pattern that was used). Responses following TBS are plotted in green (waveform and graph points), and control responses from the other stimulating electrode are plotted in black (waveforms and graph points). In B, C, F, G, H, I, the example waveforms represent a 20-min average of the pre-TBS responses, which are plotted as dotted lines of the matching color, and the 20-min average of the responses beginning 180 min post-TBS, which are plotted as solid lines. In D and E, the left most waveforms are comparisons between the pre-TBS 20-min period and at time 60 min, whereas the last set are comparisons from 180 min post-TBS. The scale bar in A is for all waveforms. B and C: no significant potentiation at postnatal day 8 (P8) (n = 4) or P9 (n = 6). D and E: short-lasting potentiation at P10 (n = 7) and P11 (n = 7). F–I: long-lasting potentiation at P12 (n = 6), P13 (n = 6), P14 (n = 6), and P15 (n = 8). J: comparison of responses at each age during the first hour (averaged from time 0–1 h) and third hour (averaged from time 3–4 h) following TBS relative to pre-TBS baseline (*post hoc P < 0.05).
Fig. 2.
Fig. 2.
Four-chamber multislice system. A: slices were viewed through 1 of the 4 camera lenses (Lens) located above each slice chamber, and electrodes were inserted into the slice through the sliding door on the top of the hood (arrow), which was custom designed to contain the humid and warm atmosphere (95% O2-5% CO2). B: example hippocampal slice with stimulating (S) and recording (R) electrodes, which were positioned at the same locations in all 4 adjacent slices. Stimulating electrodes were wrapped with sleeves made of filter paper (P) to prevent condensation from dripping on the slices. C: each TBS comprised 8 trains delivered at 30-s intervals (top) with each train having 10 bursts delivered at 5 Hz and each burst having 4 pulses delivered at 100 Hz (bottom). D: stimulation protocols were independently controlled for each slice. Example stimulation paradigms are illustrated as follows: a: test pulses given at 1 pulse per 2 min (1 p/2 min); b: test pulses given at 1 p/5 min (see Fig. 3); c: one TBS (T1) applied at 1 h after the start of test-pulse stimulation given at 1 p/5 min (e.g., see Fig. 4); d: 2 TBS applied at 1 h (T1) and 2.5 h (T2) after the start of test-pulse stimulation given at 1 p/5 min (e.g., see Fig. 5); e: 2 TBS applied at 1 h and 3 h after the start of test-pulse stimulation given at 1 p/5 min (e.g., see Fig. 7).
Fig. 3.
Fig. 3.
Frequency and age dependence of synaptic depression induced by test-pulse stimulation. A: fEPSP slopes were normalized to the first naïve response at time 0. This graph illustrates that the synaptic depression induced by test pulses at different rates in animals aged P8–12 was significantly reduced at 1 p/5 min by 4–5 h (n = 5; *P < 0.05). B: response depression induced by test-pulse stimulation at 1 p/5 min in animals of different ages. (All data are expressed as means ± SE across animals at each age and time point, with 1 slice per animal: P8–9, n = 19; P10, n = 6; P11, n = 7; P12, n = 7; P13–15, n = 7; P19–35, n = 6.) C: hourly analysis of age-dependent test pulse-induced depression at the stimulation rate of 1 p/5 min (***P < 0.001, dashed line at 80%).
Fig. 4.
Fig. 4.
TBS first produced late phase of long-term potentiation (L-LTP) at P12. TBS (delivered at time 0, green arrow) only reversed the test pulse-induced depression at P8–9 (n = 12) (A), P10 (n = 6) (B), and P11 (n = 7) (C). D: at P12, TBS produced slow-onset L-LTP, which plateaued at ∼40% between 2–3 h after TBS (n = 7). E: at P13–15, LTP onset was immediate, resulting in L-LTP (n = 6). F: similarly, at P19–35 (n = 6), L-LTP had a fast onset, and the magnitude was nearly twice that attained at P12–15. The fEPSP slopes were normalized relative to the first naïve response and then averaged across experiments and expressed as means ± SE for each age. Legend is for the example waveforms displayed in each graph, where waveforms are displayed for control (black) and TBS (green) conditions at −60, 120, and 240 min relative to TBS, with scale bars at 1 mV per 10 ms. Similarly, the black graph points represent average (means ± SE) control responses, and the green graph points are for average responses (means ± SE) before and after TBS.
Fig. 5.
Fig. 5.
A second TBS produced L-LTP at younger ages than a single TBS. A: at P8–9 (n = 20), 2 TBS (red arrows) reversed test-pulse depression but produced no L-LTP. At P10 (n = 10) (B) and P11 (n = 6) (C), only the second TBS resulted in L-LTP. D: at P12 (n = 12), 2 TBS induced a subtle late increase in the amount of L-LTP. Relative to 1 TBS, 2 TBS markedly enhanced the magnitude of L-LTP at P13–15 (n = 8) (E), but less so at P19–35 (n = 6) (F). Each data point represents mean ± SE at each time point across animals at each age. The first TBS (T) was applied at time 0, 1 h after the onset of baseline stimulation (time −60); the second TBS was applied 90 min later (T90T, red). Data from the neighboring slice that received just one TBS (T) are plotted for comparison (green), as are data from another neighboring slice that received control (CTRL) stimulation only. Legend is for the example waveforms displayed in each graph for control (black waveforms and plots), 1 TBS (green waveforms and plots), and 2 TBS (red waveforms and plots) conditions; waveforms are displayed at −60, 120, and 240 min relative to the first TBS, with scale bars for 1 mV per 10 ms.
Fig. 6.
Fig. 6.
Summary analyses comparing the developmental onset of L-LTP in response to 1 or 2 bouts of TBS. A: L-LTP onset age is P12 in response to a single TBS (T). B: metaplasticity of L-LTP following a second TBS in the T90T interval reveals significant L-LTP at P10 and P11, and greater LTP at P12–15 in the T90T interval relative to the T interval shown in A. (The dashed gray line is 120%, ***P < 0.001.)
Fig. 7.
Fig. 7.
2-Amino-5-phosphonovaleric acid (APV) blocked the L-LTP normally produced by 2 TBS delivered at time 0 and 90 min (black arrows) at P10–11 (n = 8) (A) and P12 (n = 4) (B). Legends: APV was added to the interface chambers at time −30 min and remained throughout the experiments (horizontal bar) to ensure stability in electrode positioning following TBS. Control (CTRL) slices showed the same level of synaptic depression in the presence of APV as those without APV (data not shown for clarity). T90T in the absence of APV (red triangles) and T90T in the presence of APV (white triangles).
Fig. 8.
Fig. 8.
Testing capacity of multiple TBS to produce L-LTP at younger ages. A: at P8–9, a second TBS was given 30 min (T30T orange, n = 4), 90 min (T90T red, n = 20), or 180 min (T180T purple, n = 4) after the first TBS; in each case test-pulse depression was reversed, but no L-LTP was produced. B: at P10–11, intervals of 60 min (T60T yellow, n = 4), 90 min (T90T red, n = 12), or 120 min (T120T blue, n = 5) all resulted in metaplasticity that produced L-LTP following the second TBS. In both graphs, average data from adjacent slices that were given a single TBS (T, green) or test pulses only (CTRL, black) are plotted for comparison.
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