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Infantile amnesia reflects a developmental critical period for hippocampal learning

Nature Neuroscience volume 19, pages 1225–1233 (2016)Cite this article

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An Erratum to this article was published on 01 July 2017

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Abstract

Episodic memories formed during the first postnatal period are rapidly forgotten, a phenomenon known as 'infantile amnesia'. In spite of this memory loss, early experiences influence adult behavior, raising the question of which mechanisms underlie infantile memories and amnesia. Here we show that in rats an experience learned during the infantile amnesia period is stored as a latent memory trace for a long time; indeed, a later reminder reinstates a robust, context-specific and long-lasting memory. The formation and storage of this latent memory requires the hippocampus, follows a sharp temporal boundary and occurs through mechanisms typical of developmental critical periods, including the expression switch of the NMDA receptor subunits from 2B to 2A, which is dependent on brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptor 5 (mGluR5). Activating BDNF or mGluR5 after training rescues the infantile amnesia. Thus, early episodic memories are not lost but remain stored long term. These data suggest that the hippocampus undergoes a developmental critical period to become functionally competent.

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Figure 1: Latent infantile memories are rapidly forgotten but reinstate later in life with reminders.
Figure 2: The latent infantile memory trace is hippocampus dependent.
Figure 3: Training at PN17 increases pTrkB and switches the ratio of GluN2B/GluN2A levels in the dorsal hippocampus.
Figure 4: BDNF is required for the formation of the latent infantile memory and for the GluN2B/GluN2A switch.
Figure 5: GluN2B- and mGluR5-dependent switch of GluN2B/GluN2A is required to form the latent infantile memory.
Figure 6: BDNF closes the infantile amnesia period.

Change history

  • 29 August 2016

    In the version of this article initially published, y-axis labels in Figures 3a,b, 4c, 5d and 6c report the “GluN2B/GluN2A ratio”; this should be changed to “GluN2A/GluN2B ratio.” The error has been corrected in the HTML and PDF versions of the article.

  • 01 July 2017

    Nat. Neurosci. 19, 1225–1233 (2016); published online 18 July 2016; corrected after print 29 August 2016 In the version of this article initially published, y-axis labels in Figures 3a,b, 4c, 5d and 6c report the “GluN2B/GluN2A ratio”; this should be “GluN2A/GluN2B ratio.” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank G. Pollonini for technical assistance. We thank P. Magistretti, F. Ansermet, K. Weiss, P. Balsam, X. Ye, F. Fiumara and G. Philips for discussions or comments on the manuscript. This work was supported by R01-MH074736 and an Agalma Foundation grant to C.M.A. and R01 NS072359 to R.D.B. A.T. was supported by a fellowship from Agalma Foundation. R.B. was supported by a fellowship from the Swiss National Science Foundation.

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Authors and Affiliations

  1. Center for Neural Science, New York University, New York, New York, USA

    Alessio Travaglia, Reto Bisaz & Cristina M Alberini

  2. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Eric S Sweet & Robert D Blitzer

  3. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Eric S Sweet

  4. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Robert D Blitzer

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  1. Alessio Travaglia
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Contributions

C.M.A. led the design and development of the study and the writing of the manuscript; R.D.B, designed the electrophysiology study; A.T., R.B., E.S.S., R.D.B. and C.M.A. designed experiments and analyzed data; A.T. carried out behavioral experiments and the majority of molecular and pharmacological experiments; R.B. carried out behavioral experiments and contributed to molecular and pharmacological experiments; E.S.S. carried out electrophysiology experiments; and A.T., E.S.S., R.D.B. and C.M.A. wrote the manuscript.

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Integrated supplementary information

Supplementary Figure 1 Short- and long-term memory retentions of adult rats.

Experimental schedule is shown above each panel. Acquisition (Acq.) and memory retention are expressed as mean latency ± s.e.m. (in seconds, s). (a) Mean latency ± s.e.m. of naïve and rats trained at PN80 (adults) and tested: (a) 30min (T1) and 1d after training (T2) [n= 11, 10, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(1,38)= 98.74, P< 0.0001. Testing F(1,38)= 3.718, P=0.0613, Interaction F(1,38)=3.894, P=0.0558; 3 independent experiments], and (b) 1d (T1) and 7d after training (T2) [n=5, 6, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(1,18)= 121.1, P< 0.0001,Testing F(1,18)= 0.2594, P= 0.6167, Interaction F(1,18)= 0.2921, P= 0.5955; 2 independent experiments]. ***P < 0.001. Latency score in Supplementary Table 10.

Supplementary Figure 2 Nociception of naive PN17 and PN24 rats.

Escape latency is expressed as mean ± s.e.m. (in seconds, s). Pain threshold in infant rats was measured by the escape latency to withdrawal from a 53 ± 1°C hotplate. The escape latency was averaged from four sessions, with an inter-session interval of 15-min. Student’s t-test revealed no significant difference between PN17 (10.1±0.8 seconds, n=6) and PN24 rats (8.2±0.9 seconds, n=6) (two-tailed t test, t =1.562, df=10, P=0.7028).

Supplementary Figure 3 Effect of training or shock-only on rat weight gain.

Gain weight compared to the weight taken immediately before training is expressed as mean ± s.e.m. (in grams, g). Training and shock-only at (a) PN17 [n= 8, 8, 8, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(2,42)= 1.332, P>0.05, Testing F(1,42)= 2515, P<0.0001, Interaction F(1,42)= 1.656, P>0.05; 3 independent experiments] or (b) PN24 [n= 8, 8, 8, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(2,42)= 0.4406, P>0.05, Testing F(1,42)= 801.7, P<0.0001, Interaction F(1,42)= 0.3349, P>0.05; 3 independent experiments] did not alter the average gain weight measured 1 d and 7 d later. Numeric values in Supplementary Table 11.

Supplementary Figure 4 The unpaired context–shock protocol failed to reinstate memory.

Experimental schedule is shown above the panel. Acquisition (Acq.) and memory retention are expressed as mean latency ± s.e.m. (in seconds, s). In the unpaired protocol, rats were exposed to the IA context similarly to the trained rats but did not receive a footshock in the dark chamber. They were returned to their home cage and, one hour later, were placed directly onto the grid floor of the dark chamber and immediately shocked (1.0 mA). The unpaired protocol failed to reinstate memory (n=8, 8, Two–way ANOVA followed by Bonferroni post hoc, Condition F(1.56,)=1.901, P=0.1735, Testing F(3,56)=4.720, P=0.0053, Interaction F(3,56)=1.245, P=0.3021; 3 independent experiments). Latency score in Supplementary Table 12.

Supplementary Figure 5 Memory reinstatement following different time intervals between test and reminder shock.

Experimental schedule is shown above the panel. Acquisition (Acq.) and memory retention are expressed as mean latency ± s.e.m. (in seconds, s). Mean latency ± s.e.m. of naïve, shock-only and rats trained at PN17, tested 7d later (T1) and given a reminder shock (RS) 4h, 1d or 7d after the test (T1). Memory retention was tested 1d (T2) and 7d (T3) after RS, and, 4d later, in a new context (NC) [n= 11, 13, 11, 11, 11, Two–way ANOVA followed by Bonferroni post hoc, Treatment F(4,208)=18.27, P<0.0001, Testing F(3,208)=26.93, P<0.0001, Interaction F(12,208)=4.269, P<0.0001; 3 independent experiments]. Latency score in Supplementary Table 13.

Supplementary Figure 6 Hippocampal molecular changes either in untrained (naïve) conditions or following IA training at PN17 or PN24.

(a) Representative examples and densitometric western blot analyses of dorsal hippocampal total extracts from naïve rats euthanized at PN17, PN24 or PN80 (adult) (n=8, 8, 8). Data are expressed as mean percentage ± s.e.m. of adult naïve rats [One–way ANOVA followed by Newman-Keuls Multiple Comparison Test, TrkB F(2,21)= 0.6080, P=0.5537; GluN1 F(2,21)= 0.1954, P=0.8240, 3 independent experiments]. (b-c) Representative examples and densitometric western blot analyses of dHC total extracts from rats trained in IA at (b) PN17 or (c) PN24, and euthanized 30min, 9h, 24h or 48h after training (n=6-10/group). To account for developmental differences, two groups of naïve were used [(b) PN17 and PN19 or (c) PN24 and PN26]. Data are expressed as mean percentage ± s.e.m. of (b) PN17 [n= 8, 6, 10, 7, 6, 6, One–way ANOVA followed by Dunnett's Multiple Comparison Test, TrkB F(3,27)= 0.1618, P= 0.9211; GluN1 F(3,27)= 0.08967, P= 0.9650; 3 independent experiments] or (c) PN24 naïve rats [n=8, 6, 6, 7, 7, 8, One–way ANOVA followed by Dunnett's Multiple Comparison Test, TrkB F(3,23)= 0.06099, P= 0.9798; GluN1 F(3,23)= 0.2067, P= 0.8907; 3 independent experiments]. The numeric values are reported in Supplementary Table 3.

Supplementary Figure 7 Hippocampal molecular changes after shock- or context-only.

Densitometry of western blot analyses of dorsal hippocampal total extracts from rats euthanized 24 hours after (a) receiving a footshock immediately after being placed on a shock grid (shock-only) [n= 7, 7, Unpaired two-tailed Student’s t-test, pTrkB t=0.3263 df=12, P = 0.7498; GluN2A t=0.5967 df=12, P = 0.5618l; GluN2B t=0.1414 df=12, P = 0.8899; 2 independent experiments] or (b) exposed to the IA context without receiving the footshock (context-only) [n= 7, 7, Unpaired two-tailed Student’s t-test, pTrkB t=0.5199 df=12, P = 0.6126; GluN2A t=0.6308 df=12, P = 0.5400; GluN2B t=0.4679 df=12 P = 0.6482; 2 independent experiment]. Data are expressed as mean percentage ± s.e.m. of naive rats euthanized at the matched time point (i.e. PN18). The numeric values are reported in Supplementary Table 14.

Supplementary Figure 8 Hippocampal molecular changes after memory reinstatement.

Experimental schedule is shown above the panel. Densitometric western blot analyses of dorsal hippocampal total extracts obtained from rats trained (Tr) at PN17, 7 days later exposed to the reinstatement protocol [test (T1) and 2d later reminder shock (RS)] and euthanized 30min or 24 hours later. Data are expressed as mean percentage ± s.e.m. of rats trained at PN17, tested (T1) but not exposed to RS and euthanized at the matched time point [n=6/group, One–way ANOVA followed by Newman-Keuls Multiple Comparison Test, pTrkB F(2,17)= 0.27, P=0.77; GluN2A F(2,17)= 0.72, P=0.50; GluN2B F(2,17)= 0.08, P=0.82; 2 independent experiment). The numeric values are reported in Supplementary Table 15.

Supplementary Figure 9 Full-length pictures of the blots presented in the main figures.

Supplementary Figure 10 Full-length pictures of the blots presented in the main figures

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Travaglia, A., Bisaz, R., Sweet, E. et al. Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat Neurosci 19, 1225–1233 (2016). https://doi.org/10.1038/nn.4348

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