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To determine the critical timing for learning and the associated synaptic plasticity, we analyzed developmental changes in learning together with training-induced plasticity. Rats were subjected to an inhibitory avoidance (IA) task prior to weaning. While IA training did not alter latency at postnatal day (PN) 16, there was a significant increase in latency from PN 17, indicating a critical day for IA learning between PN 16 and 17. One hour after training, acute hippocampal slices were prepared for whole-cell patch clamp analysis following the retrieval test. In the presence of tetrodotoxin (0.5 µM), miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) were sequentially recorded from the same CA1 neuron. Although no changes in the amplitude of mEPSCs or mIPSCs were observed at PN 16 and 21, significant increases in both excitatory and inhibitory currents were observed at PN 23, suggesting a specific critical day for training-induced plasticity between PN 21 and 23. Training also increased the diversity of postsynaptic currents at PN 23 but not at PN 16 and 21, demonstrating a critical day for training-induced increase in the information entropy of CA1 neurons. Finally, we analyzed the plasticity at entorhinal cortex layer III (ECIII)-CA1 or CA3-CA1 synapses for each individual rat. At either ECIII-CA1 or CA3-CA1 synapses, a significant correlation between mean α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartic acid (AMPA/NMDA) ratio and learning outcomes emerged at PN 23 at both synapses, demonstrating a critical timing for the direct link between AMPA receptor-mediated synaptic plasticity and learning efficacy. Here, we identified multiple critical periods with respect to training-induced synaptic plasticity and delineated developmental trajectories of learning mechanisms at hippocampal CA1 synapses.

Adolescence is the critical postnatal stage for the action of androgen in multiple brain regions. Androgens can regulate the learning/memory functions in the brain. It is known that the inhibitory avoidance test can evaluate emotional memory and is believed to be dependent largely on the amygdala and hippocampus. However, the effects of androgen on inhibitory avoidance memory have never been reported in adolescent male rats. In the present study, the effects of androgen on inhibitory avoidance memory and on androgen receptor (AR)-immunoreactivity in the amygdala and hippocampus were studied using behavioral analysis, Western blotting and immunohistochemistry in sham-operated, orchiectomized, orchiectomized + testosterone or orchiectomized + dihydrotestosterone-administered male adolescent rats. Orchiectomized rats showed significantly reduced time spent in the illuminated box after 30 min (test 1) or 24 h (test 2) of electrical foot-shock (training) and reduced AR-immunoreactivity in amygdala/hippocampal cornu Ammonis (CA1) in comparison to those in sham-operated rats. Treatment of orchiectomized rats with either non-aromatizable dihydrotestosterone or aromatizable testosterone were successfully reinstated these effects. Application of flutamide (AR-antagonist) in intact adolescent rats exhibited identical changes to those in orchiectomized rats. These suggest that androgens enhance the inhibitory avoidance memory plausibly by binding with AR in the amygdala and hippocampus.