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Infantile Amnesia Is Related to Developmental Immaturity of the Maintenance Mechanisms for Long-Term Potentiation

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Abstract

Infantile amnesia (IA) refers to the inability of adults to recall episodic memories from infancy or early childhood. While several hypotheses have been proposed to explain the occurrence of IA, the neurobiological and molecular bases for this accelerated forgetting phenomenon remain elusive. Using hippocampus-dependent object-location memory and contextual fear conditioning tasks, we confirmed that infant mice trained at postnatal day 20 (P20) displayed deficits in long-term memory retention compared to adult (P60) mice. The percentage of CA1 pyramidal neurons expressing phosphorylated cAMP-responsive element-binding protein after fear conditioning was significantly lower in P20 than P60 mice. P20 mice exhibited attenuated basal excitatory synaptic transmission and early-phase long-term potentiation (E-LTP) at Schaffer collateral-CA1 synapses compared to P60 mice, but conversely, P20 mice have a greater susceptibility to induce time-dependent reversal of LTP by low-frequency afferent stimulation than P60 mice. The protein levels of GluN2B subunit of N-methyl-d-aspartate receptors (NMDARs), protein kinase Mζ (PKMζ), and protein phosphatase 2B (PP2B) in hippocampal CA1 region were significantly higher in P20 than P60 mice. We also found that the levels of calcium/calmodulin-dependent protein kinase II α autophosphorylation at Thr286, GluA1 phosphorylation at Ser831, and PKMζ protein biosynthesis occurred during the ensuing maintenance of E-LTP were significantly lower in P20 than P60 mice. Pharmacological blockade of GluN2B-containing NMDARs or PP2B effectively restored deficits of E-LTP and long-term memory retention observed in P20 mice. Altogether, these findings suggest that developmental immaturity of the maintenance mechanisms for E-LTP is linked to the occurrence of IA.

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Acknowledgements

We thank the technical services provided by the Bio-image Core Facility of the National Core Facility Program for Biotechnology, Ministry of Science and Technology, Taiwan.

Funding

This work was supported by research grants from the Ministry of Science and Technology (MOST 106-2320-B-006-026-MY3) and the National Health Research Institute (NHRI-EX106-10613NI and NHRI-EX107-10713NI), Taiwan.

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Authors and Affiliations

  1. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Tsung-Chih Tsai & Kuei-Sen Hsu

  2. Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd, Tainan, 701, Taiwan

    Chiung-Chun Huang & Kuei-Sen Hsu

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  1. Tsung-Chih Tsai
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Correspondence to Kuei-Sen Hsu.

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All experimental procedures complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of National Cheng Kung University.

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The authors declare that they have no conflict of interest.

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Tsai, TC., Huang, CC. & Hsu, KS. Infantile Amnesia Is Related to Developmental Immaturity of the Maintenance Mechanisms for Long-Term Potentiation. Mol Neurobiol 56, 907–919 (2019). https://doi.org/10.1007/s12035-018-1119-4

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