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PO1-1-10

Developmental immaturity of the maintenance mechanisms for long-term potentiation is functionally linked to infantile amnesia

[Speaker] Tsung-Chih Tsai:1
[Co-author] Chiung-Chun Huang:1, Kuei-Sen Hsu:1,2
1:The Institute of Basic Medical Sciences, National Cheng Kung University, Taiwan, 2:Department of Pharmacology, College of Medicine, National Cheng Kung University, Taiwan

Background: 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.

Methods: Hippocampus-dependent object-location memory and contextual fear conditioning tasks were used to compare the retention of long-term memory in infant mice trained at postnatal day 20 (P20) and adult mice at P60. Extracellular field potentials and whole-cell patch-clamp recordings were used to compare the basal synaptic transmission and the induction of long-term potentiation (LTP) in slices from P20 and P60 mice. Western blotting was performed to compare the expression profiles of protein kinases and phosphatases in hippocampal CA1 tissues lysates from P20 and P60 mice.

Results: P20 mice displayed deficits in long-term memory retention compared to P60 mice. 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 (LTP) at Schaffer collateral-CA1 synapses compared to P60 mice, but conversely the susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was facilitated in P20 mice. The protein levels of GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), protein kinase Mzeta (PKMzeta) 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 IIalpha; autophosphorylation at Thr286, GluA1 phosphorylation at Ser831 and PKMzeta 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 rescued the deficits of E-LTP and long-term memory retention observed in P20 mice.

Conclusions: Our results suggest that developmental immaturity of the maintenance mechanisms for E-LTP is functionally linked to the occurrence of IA. These findings may contribute a better understanding neurobiological mechanisms underlying IA and provide novel pharmacological strategies to reduce rate of forgetting.
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