The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABA_A (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABA_A receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABA_A receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABA_A receptor trafficking, synaptic E/I imbalance and neuronal excitability.

Postnatal development of hippocampal function has been reported in many mammalian species, including humans. To obtain synaptic evidence, we analyzed developmental changes in plasticity after an inhibitory avoidance task in rats. Learning performance was low in infants (postnatal 2 weeks) but clearly improved from the juvenile period (3–4 weeks) to adulthood (8 weeks). One hour after the training, we prepared brain slices and sequentially recorded miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) from the same hippocampal CA1 neuron. Although the training failed to affect the amplitude of either mEPSCs or mIPSCs at 2 weeks, it increased mEPSC, but not mIPSC, amplitude at 3 weeks. At 4 weeks, the training had increased the amplitude of both mEPSCs and mIPSCs, whereas mIPSC, but not mEPSC, amplitude was increased at 8 weeks. Because early-life physiological functions can affect performance, we also evaluated sensory–motor functions together with emotional state and found adequate sensory/motor functions from infancy to adulthood. Moreover, by analyzing performance of rats in multiple hippocampal-dependent tasks, we found that the developmental changes in the performance are task dependent. Taken together, these findings delineate a critical period for learning and plastic changes at hippocampal CA1 synapses.

Aβ_1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer’s disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ_1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ_1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (I_NaP) blocker, dose-dependently reduced Aβ_1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ_1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

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.