Tsui J et al. (2010), A developmental sensitive period for spike timi...

XB-ART-43613

Front Synaptic Neurosci 2010 Jun 10;2:13. doi: 10.3389/fnsyn.2010.00013.

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A developmental sensitive period for spike timing-dependent plasticity in the retinotectal projection.

Tsui J , Schwartz N , Ruthazer ES .

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The retinotectal projection in Xenopus laevis has been shown to exhibit correlation-based refinement of both anatomical and functional connectivity during development. Spike timing-dependent plasticity (STDP) is an appealing experimental model for correlation-based synaptic plasticity because, in contrast to plasticity induction paradigms using tetanic stimulation or sustained postsynaptic depolarization, its induction protocol more closely resembles natural physiological activity. In Xenopus tadpoles, where anatomical remodeling has been reported throughout much of the life of the animal, in vivo retinotectal STDP has only been examined under a limited set of experimental conditions. Using perforated-patch recordings of retina-evoked EPSCs in tectal neurons, we confirmed that repeatedly driving a retinotectal EPSP 5-10 ms prior to inducing an action potential in the postsynaptic cell, reliably produced timing-dependent long-term potentiation (t-LTP) of the retinotectal synapse in young wild type tadpoles (stages 41-44). At these stages, retinotectal timing-dependent long-term depression (t-LTD) also could be induced by evoking an EPSP to arrive 5-10 ms after an action potential in the tectal cell. However, retinotectal STDP using this standard protocol was limited to a developmental sensitive period, as we were unable to induce t-LTP or t-LTD after stage 44. Surprisingly, this STDP protocol also failed to induce reliable STDP in albino tadpoles at the early ages when it was effective in wild type pigmented animals. Nonetheless, low-frequency flashes to the eye produced a robust NMDA receptor-dependent retinotectal LTD in stage 47 albino tadpoles, demonstrating that the retinotectal synapse can nonetheless be modified in these animals using different plasticity paradigms.

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Species referenced: Xenopus laevis
Genes referenced: tbx2

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	Figure 1. Protocols for inducing STDP. (A) Schematic of in vivo recording set-up. (B) Representative tectal response to retinal stimulation. Scale bar is 5pA and 5 ms. Black line indicates beginning of 100-ms stimulus and gray box indicates stimulus artifact. (C) t-LTP protocol. A 2 ms 0.17–0.2 pA current pulse was injected in the post-synaptic tectal cell to evoke an action potential 5–10 ms following the onset of the EPSC. (D) t-LTD protocol. The stimulating electrode in the retina was timed to evoke an EPSC 5–10 ms after an action potential in the tectal neuron. (E) In the control conditioning protocol, this timing window was lengthened to 100 ms, outside the described window for plasticity at this synapse (Zhang et al., 1998). A 20–60 ms hyperpolarizing current pulse was timed to prevent action potential firing due to the retinal EPSC. Traces are from cells held at −40 to −50 mV in current clamp. Scale bar is 10 mV and 20 ms.
	Figure 2. Spike timing-dependent LTP is limited to a sensitive period ending around stage 45 in wild type tadpoles. (A) Experiment in a stage 43 tadpole in with t-LTP was induced (arrow) using a 5–10 ms preàpost pairing interval. Inset shows averaged EPSC before (black) and 20–30 min after (red) t-LTP induction. (B) Example from stage 46 animal lacking t-LTP. (C) Averages of t-LTP induction experiments in stage 41–44 (filled circles, n = 4) and stage 46–47 (open circles, n = 4) tadpoles. (D) Control (100-ms interval) pairing did not induce reliable STDP at any age (stage 41–44, n = 7; stage 46–47, n = 5). (E) Graph summarizing t-LTP experiments by age. †p < 0.05 one-sample t-test (0–10 vs. 30–40 min), *p < 0.05 ANOVA with Bonferroni post-test.
	Figure 3. The sensitive period for spike timing-dependent LTD is similar to that for t-LTP. (A) Experiment from a stage 41 tadpole in which t-LTD was induced (arrow) using the 5–10 ms postàpre protocol. (B) The same pairing protocol failed to induce synaptic depression in a stage 45 tadpole. Insets show sample traces as in Figure 1. (C) Average of all t-LTD experiments grouped by developmental stage. (D) Graph summarizing t-LTD experiments by developmental stage. n = 7 stage 41–44, n = 6 stage 45–47, †p < 0.05 one-sample t-test (0–10 vs. 30–40 min), **p < 0.01 Student's t-test.
	Figure 4. Scatterplot showing STDP efficacy as a function of developmental stage. Mean EPSC amplitude measured at 20–30 min after induction, normalized to baseline amplitude during the 10 min immediately prior to induction.
	Figure 5. Albino Xenopus tadpoles do not exhibit reliable STDP during the sensitive period. (A–C) Average of experiments to induce t-LTP (n = 4) (B) and t-LTD (n = 4) (C) using the protocols that succeeded in wild type animals, applied to stage 41–44 albino tadpoles. No STDP was reliably generated using the classic STDP protocol in albinos.
	Figure 6. Repeated low-frequency visual stimulation induced LTD in albino stage 47 tadpoles. (A) Repeatedly flashing an array of LEDs at 1 Hz for 15 min induced retinotectal synaptic depression. (B) This visual stimulation induced LTD was largely blocked in the presence of CPP (40 mM). (C) Average of all experiments with (filled circles, n = 4) and without (open circles, n = 9) NMDARs pharmacologically blocked. p < 0.001 Student's t-test.

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