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

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.

Social Transmission and Buffering of Hippocampal Metaplasticity after Stress in Mice

“…Hippocampal cannula implantation and drug injection. Mice were bilaterally implanted under deep pentobarbital (50 mg/kg, i.p., supplemented as required) anesthesia with 28 gauge guide cannulas (Plastics One) in the dorsal hippocampus as previously described (Tsai et al, 2019). Coordinates for mice were À2.3 mm posterior to bregma, 61.5 mm bilateral to midline, and 1.8 mm ventral to brain surface according to adult mouse brain stereotaxic atlas (Franklin and Paxinos, 2008).…”

Development of Depotentiation in Adult-Born Dentate Granule Cells

“…Similar to LTP reversal deficiency in juvenile mice, juvenile animals learn faster than adult animals. A recent report showed by using hippocampus-dependent object-location memory and contextual fear conditioning tasks confirmed that juvenile mice displayed deficits in long-term memory retention compared with adult mice (Tsai et al, 2018), which was probably because juvenile mice have insufficient memory encoding (Ge et al, 2019).…”

Behind the scenes: Are latent memories supported by calcium independent plasticity?

“…The cellular, molecular, and electrophysiological constraints of infantile amnesia are not fully known. Prior to P21, LTP is more difficult to induce (Blair et al, 2013; Dumas, 2012) and dissipates more rapidly (Harris & Teyler, 1984; Tsai, Huang, & Hsu, 2019; Yasuda, Barth, Stellwagen, & Malenka, 2003). It is possible that after IA training at this age, the context‐shock association is encoded through a developmental form of “fragile” LTP, which could support memory retrieval at short time periods following behavior training (Travaglia et al, 2016).…”