Memories are stored in synapses that consist of axon terminals and dendritic spines.Dendritic spines are postsynaptic structures of synapses and are essential for synaptic plasticity and cognition. Therefore, extensive investigations concerning the functions and structures of spines have been performed. Sex steroids and stress steroids have been shown to modulate hippocampal synapses. Although the rapid modulatory action of sex steroids on synapses has been studied in hippocampal neurones over several decades, the essential molecular mechanisms have not been fully understood.Here, a description of kinase-dependent signalling mechanisms is provided that can explain the rapid nongenomic modulation of dendritic spinogenesis in rat and mouse hippocampal slices by the application of sex steroids, including dihydrotestosterone, testosterone, oestradiol and progesterone. We also indicate the role of synaptic (classic) sex steroid receptors that trigger these rapid synaptic modulations. Moreover, we describe rapid nongenomic spine modulation by applying corticosterone, which is an acute stress model of the hippocampus. The explanations for the results obtained are mainly based on the optical imaging of dendritic spines. Comparisons are also performed with results obtained from other types of imaging, including electron microscopic imaging. Relationships between spine modulation and modulation of cognition are discussed. We recognise that most of rapid effects of exogenously applied oestrogen and androgen were observed in steroid-depleted conditions, including acute slices of the hippocampus, castrated male animals and ovariectomised female animals. Therefore, the previously observed effects can be considered as a type of recovery event, which may be essentially similar to hormone replacement therapy under hormone-decreased conditions. On the other hand, in gonadally intact young animals with high levels of endogenous sex hormones, further supplementation of sex hormones might not be effective, whereas the infusion of blockers for steroid receptors or kinases may be effective, with respect to suppressing sex hormone functions, thus providing useful information regarding molecular mechanisms. K E Y W O R D Sandrogens, cortisol/corticosterone, glucocorticoids, membrane/nuclear receptors, neuroactive steroids, oestrogens, steroids

d-Aspartate (d-Asp), the stereoisomer of l-aspartate, has a role in memory function in rodents. However, the mechanism of the effect of d-Asp has not been fully understood. In this study, we hypothesized that ingested d-Asp directly reaches the hippocampal tissues via the blood circulation and modifies the functional connectivity between hippocampus and other regions through spinogenesis in hippocampal CA1 neurons. The spinogenesis induced by the application of d-Asp was investigated using rat acute hippocampal slices. The density of CA1 spines was increased following 21 and 100 μM d-Asp application. The nongenomic spine increase pathway involved LIM kinase. In parallel to the acute slice study, brain activation was investigated in awake rats using functional MRI following the intragastric administration of 5 mM d-Asp. Furthermore, the concentration of d-Asp in the blood serum and hippocampus was significantly increased 15 min after intragastric administration of d-Asp. A functional connectivity by awake rat fMRI demonstrated increased slow-frequency synchronization in the hippocampus and other regions, including the somatosensory cortex, striatum, and the nucleus accumbens, 10-20 min after the start of d-Asp administration. These results suggest that ingested d-Asp reaches the brain through the blood circulation and modulates hippocampal neural networks through the modulation of spines.

Perinatal exposure to Bisphenol A (BPA) at a very low dose may modulate the development of synapses of the hippocampus during growth to adulthood. Here, we demonstrate that perinatal exposure to 30 μg BPA/kg per mother’s body weight/day significantly altered the dendritic spines of the grownup rat hippocampus. The density of the spine was analyzed by imaging of Lucifer Yellow-injected CA1 glutamatergic neurons in adult hippocampal slices. In offspring 3-month male hippocampus, the total spine density was significantly decreased by BPA exposure from 2.26 spines/μm (control, no BPA exposure) to 1.96 spines/μm (BPA exposure). BPA exposure considerably changed the normal 4-day estrous cycle of offspring 3-month females, resulting in a 4∼5 day estrous cycle with 2-day estrus stages in most of the subjects. In the offspring 3-month female hippocampus, the total spine density was significantly increased by BPA exposure at estrus stage from 2.04 spines/μm (control) to 2.25 spines/μm (BPA exposure). On the other hand, the total spine density at the proestrus stage was moderately decreased from 2.33 spines/μm (control) to 2.19 spines/μm (BPA exposure). Thus, after the perinatal exposure to BPA, the total spine density in males became lower than that in females. Concerning the BPA effect on the morphology of spines, the large-head spine was significantly changed with its significant decrease in males and moderate change in females.

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Dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from an axon terminal at the synapse. Memories are stored in synapses which consist of spines and presynapses. Rapid modulations of dendritic spines induced by hippocampal sex steroids, including dihydrotestosterone (DHT), testosterone (T), and estradiol (E2), are essential for synaptic plasticity. Molecular mechanisms underlying the rapid non-genomic modulation through synaptic receptors of androgen (AR) and estrogen (ER) as well as its downstream kinase signaling, however, have not been well understood. We investigated the possible involvement of Src tyrosine kinase in rapid changes of dendritic spines in response to androgen and estrogen, including DHT, T, and E2, using hippocampal slices from adult male rats. We found that the treatments with DHT (10 nM), T (10 nM), and E2 (1 nM) increased the total density of spines by ~1.22 to 1.26-fold within 2 h using super resolution confocal imaging of Lucifer Yellow-injected CA1 pyramidal neurons. We examined also morphological changes of spines in order to clarify differences between three sex steroids. From spine head diameter analysis, DHT increased middle- and large-head spines, whereas T increased small- and middle-head spines, and E2 increased small-head spines. Upon application of Src tyrosine kinase inhibitor, the spine increases induced through DHT, T, and E2 treatments were completely blocked. These results imply that Src kinase is essentially involved in sex steroid-induced non-genomic modulation of the spine density and morphology. These results also suggest that rapid effects of exogenously applied androgen and estrogen can occur in steroid-depleted conditions, including “acute” hippocampal slices and the hippocampus of gonadectomized animals.