steroid hormones have been traditionally associated with regulation of peripheral organs , associated with stress ( corticosterone ) or with gonadal function ( estrogen and androgens ) . over the years , it became evident that these hormones also act within the hypothalamus , in a feedback regulatory loop , to affect the release of the neural factors that modulate production of the steroid hormones . more recently , several observations have elucidated new roles of steroid hormones in modulating higher cns functions . specifically , both stress and steroid hormones have been shown to affect synaptic receptors and ion channels and therefore regulate in several different ways synaptic transmission and neuronal plasticity . consequently , stress hormones have been implicated in processes ranging from homeostatic to cognitive functions . furthermore , in some disorders of the nervous system , hormones have been shown to play critical roles : favoring or halting the disease process . thus , the interaction between peripheral hormones and central networks seem to be more intense than ever imagined before . in the present study we review current knowledge on the effects of steroid hormones on synaptic plasticity and define their influence on hippocampal cognitive and emotional functions . following the exposure to stressful stimuli , the steroid hormone corticosterone ( cortisol in humans ) is released from the adrenal glands in order to set up the best response to the challenge by acting on steroid receptors ( de kloet et al . , 2005 ) . these are distributed throughout the body and have a particularly dense distribution in the cns ( de kloet et al . , 2005 ) . in the brain , the cellular and molecular targets for the action of corticosterone include , in addition to basic metabolic processes , an effect on excitatory ( karst and joels , 2005 ) and inhibitory ( maggio and segal , 2009a ) synaptic transmission , as well as an effect on voltage - gated calcium channels ( vgcc ; karst et al . , 2000 ; these effects are mediated by the activation of mineralocorticoid receptors ( mrs ) and glucocorticoid receptors ( grs ; joels , 1999 , 2008 ; de kloet et al . , 2005 ) . initially , it was suggested that both receptors act as nuclear transcription factors that modify protein synthesis and produce a slow , persistent change in the function of the cell ( de kloet et al . more recently , the existence of a new family of membrane - bound mr and gr ( mmr and mgr , respectively ) , which act through novel non - genomic pathways , has been reported ( karst et al . , 2005 ; de kloet et al . , 2008 ) . in this route , mmr and mgr can rapidly affect ionic conductances and thereby modify cell excitability and function ( karst et al . these membrane - bound receptors appear to differ from their intracellular cognates , not only in their location on the cell membrane , but also in their molecular structures ( joels et al . , 2008 ) , in their affinities for corticosterone , and in their downstream mechanisms of action which involve activation of g proteins ( joels et al . , 2008 ) . specifically , intracellular mr ( imr ) have a very high affinity for corticosterone and are highly expressed in all hippocampal subfields , as well as in cells of the central amygdala , lateral septum , and some motor nuclei in the brainstem ( joels , 2006 ) . intracellular gr ( igr ) have a relatively low affinity , are widely distributed throughout the brain , and are expressed both in neurons and in glia ( joels , 2006 ) . consequently , it has been proposed that imr hardly participate , if at all , in the fast response to stressful stimuli , due to their characteristic of being already saturated by the low ambient levels of corticosterone at rest ( joels , 2006 , 2008 ) . conversely , igr have been reported to become gradually activated by rising levels of corticosterone following a stressful event ( joels , 2006 , 2008 ; figure 1a ) . therefore , under physiological conditions , cells that coexpress both receptor types , such as principal cells in the ca1 region , the dentate gyrus ( dg ) , and the central amygdala , will shift between predominant imr activation and concurrent mmr and igr activation ( joels and krugers , 2007 ) . ( a ) time course of mr and gr activation following stressful stimuli . at a resting level , imr are already saturated by the baseline levels of corticosterone . rising concentration of corticosterone activates both mmr and igr , whereas an additional increase in corticosterone levels also activates mgr . mmr- and mgr - mediated effects appear in a faster time course than those mediated by the intracellular receptors . modified from maggio and segal ( 2010 ) . ( b ) proposed mechanism by which corticosteroid receptors differently regulate ltp and ltd in the hippocampus . imr are believed to be fully occupied at baseline level of corticosterone , therefore they might play a marginal role in synaptic plasticity . mmr might play a fundamental role in synaptic plasticity especially in vh : mmr activation reduces ipsc frequency . this determines an increase in the excitability of the pyramidal cells and raises the possibility of vgcc activation , thus enhancing ltp . in addition , a decrease in gabaergic inhibition can impair ltd through a group i mglur - mediated mechanism . igr are thought to both decrease nmda - mediated ltp and increase vgccs mediated ltp both in the hippocampus and amygdale . their effects may occur at longer time scale due to their lower affinity to corticosterone . mgr might be involved in the regulation of synaptic plasticity mainly in dh : mgr activation increases ipsc amplitude and following hyperpolarization of the pyramidal cell membrane and inactivation of nmda receptors , might impair ltp and enhance ltd . modified from maggio and segal ( 2010 ) . the identification of the molecular cascades linked to the effects of corticosteroids in the brain resulted in a series of studies examining the role of corticosterone in neuronal plasticity as well as in the cellular mechanisms underlying learning and memory such as long - term potentiation ( ltp ) and long - term depression ( ltd ; bliss and collingridge , 1993 ) . initial studies indicated that induction of ltp in the hippocampal area ca1 is impaired in a rat exposed to behavioral stress , such as inescapable shock ( foy et al . administration of high doses of corticosterone either in vivo ( diamond et al . , 1992 ) or in vitro ( pavlides et al . , 1996 ; alfarez et al . , 2002 ) produced the same effects , indicating that corticosterone is likely to mediate this action of stress . specifically , corticosterone - induced impairment of ltp seems to be due to the activation of igr , which depresses nmda receptor - dependent ltp ( krugers et al . conversely , it was also shown that ltp could be enhanced in the presence of low to moderate concentrations of corticosterone , while in absence of corticosterone ltp induction was impaired ( diamond et al . , 1992 ) . these studies show that the effects of corticosteroids on ltp induction are dose - dependent and follow an inverted u - shaped relationship ( diamond et al . , 1992 ; joels , 2006 ) . further studies , however , have presented a more complex picture of the effects of steroids on synaptic plasticity . specifically , it seems that the same dosage of corticosterone that impairs nmda - dependent ltp can indeed enhance vgcc - dependent ltp ( krugers et al . , 2005 ) . this species of ltp is found in the amygdale where it is believed to underlie the formation of fear memories ( blair et al . , 2001 ; bauer et al . , 2002 ) and can be evoked in the hippocampus as well ( borroni et al . , 2000 ; interestingly , in the hippocampus , corticosterone appears to enhance vgcc ltp through an igr - dependent mechanism ( krugers et al . , 2005 ) . it has been proposed that this effect requires a genomic pathway , as it occurs after a long delay between the exposure to stress and/or corticosterone and the recordings ( krugers et al . , 2005 ) , thus probably depending on the binding of gr homodimers to dna that causes an increase in calcium currents ( karst and joels , 2005 ; chameau et al . , 2007 ) . recent data from our group have shown that mrs are also able to enhance vgcc ltp ( maggio and segal , 2007b ) : either stress or physiological concentrations of corticosterone can enhance ltp in the ventral hippocampus ( vh ) , while inhibiting it in the dorsal hippocampus ( dh ; maggio and segal , 2007b ) . in particular , corticosterone enhances ltp through mrs since a selective mr agonist , aldosterone , shares the same effect in the vh ( maggio and segal , 2007b ) . the proposed mechanism excludes an interaction between mr and nmda receptors , as aldosterone by itself does not increase nmda - dependent synaptic potentials ( maggio and segal , 2007b ) . conversely , mr - induced ltp can be blocked by nifedipine , suggesting that vgccs are likely responsible for this effect ( maggio and segal , 2007b ; figure 1b ) . it is likely that mr activates vgcc by modulating ionic conductances or changing vgcc activation kinetics . in vivo experiments have shown that mr activation is able to increase ltp in the dh as well ( avital et al . , 2006 ) . specifically , animals which were injected with a gr antagonist prior to the stressful exposure , such that only mr could be activated by stress , show a much larger ltp than controls . in contrast , those animals previously injected with an mr antagonist and then exposed to stress , allowing only gr activation , show a much lower ltp than controls ( avital et al . , 2006 ) . these recordings were performed in the dg and even though there could be differences in the effects of stress and steroids between the dg and ca1 ( joels and krugers , 2007 ) , mrs were still shown to mediate an enhancement of ltp . it could be argued that the experiments in the vh were conducted using an in vitro preparation where ambient corticosterone maintained normally through the circulation is washed out . consequently , mrs are not occupied , and are ready to be activated by the superfused drug and produce ltp enhancement in the vh . this might not reflect the situation in the intact animal , where the brain is constantly exposed to fluctuating concentrations of corticosterone . in fact , mr should be already saturated by the resting concentration of corticosterone and should not respond to the stress - induced rise of corticosterone in the presence of a gr blockade . this , however , does not seem to be the case ( avital et al . , 2006 ) . furthermore , even though both mr and gr are expressed in the vh , corticosterone action is mediated by activation of mr rather than gr . this reflects the observation that in the vh , mr concentration is double that of gr ( robertson et al . , 2005 ) . if so , according to the u - shaped curve model of corticosterone effects , mr should be saturated rapidly by the rising concentration of corticosterone and their effect should fade away faster in favor of the slower gr activation . altogether , it seems that the simple , dose - dependent , inverted , u - shaped curve does not fully explain the modulatory functions of mr and gr on ltp in the different sectors of the hippocampus , therefore calling for the involvement of other factors . a possible mechanism that may clarify the mr - dependent enhancement of ltp should take into consideration the activation of mmr . these receptors act through a faster mechanism ( de kloet et al . , 2008 ) and have lower affinities for corticosterone compared to their intracellular cognates ( joels , 2008 ) and similar to that of the igr ( joels , 2008 ) . in addition , mr activation enhances ltp in the vh within 1 h , too short time window to be accounted for by activation of genomic mechanisms ( joels and krugers , 2007 ; joels , 2008 ) , but compatible with the faster time course of the non - genomic routes . thus , mmr could be the preferential target for rising concentrations of corticosterone in the vh if one takes into account the similar affinities for corticosterone between mmr and igr , and the denser distribution of the former over the latter ( robertson et al . this could most likely be due to the shorter time window of observation in our experiments compared to those done by others ( krugers et al . , both mr and gr were reported to increase vgcc ltp ( krugers et al . , 2005 ; maggio and segal , 2007b ) . this apparent contrast could probably be explained by considering the different time courses of mr and gr enhancement of vgcc ltp . specifically , mr has an earlier effect than gr and it could be that in the vh stress mediates a fast enhancement of ltp by mr followed by a second , slow increase in ltp due to gr activation . this proposal is compatible with the proposed role of the vh as a key player in the pathway that conveys stressful information to the hypothalamus and the amygdale so as to organize the stress response ( moser and moser , 1998 ; maggio and segal , 2010 ; segal et al . , 2010 ) . following stress , the quick mr - mediated increase in ltp facilitates the flow of the information related to stress from the vh to the ventral hypothalamus and other lower brain centers , so that the autonomic response to stress can be organized . later on , the mr - mediated response fades away and the effect of gr dominates . as previously mentioned , gr enhancement of vgcc ltp has been shown to have a role in the formation of fear memories in the amygdale ( blair et al . , 2001 ; bauer et al . , , gr could play the same function in the vh : the formation of the memory for the stressful event at the vh indeed , the evidence that mr and gr act on the same mechanism can have different purposes due to the time window of the respective outcomes that take place . considering this , it could be interesting to study the relationship between the mr and gr responses in the vh . in the dh , the reduction of ltp is mediated by gr ( maggio and segal , 2007b ) . this effect seems to occur in less than 1 h , a relatively quick response that is unlikely to be mediated by a genomic mechanism . gr could reduce nmda - mediated ltp either by a direct or an indirect mechanism . as far as it concerns the indirect mechanism hypothesis , we have demonstrated that a gr agonist , dexamethasone , increases ipscs and mipscs amplitude in the dh within 10 min ( maggio and segal , 2009a , 2012 ) , consistent with the possible activation of mgr . therefore , the increase in gabaa conductance could hyperpolarize the membrane , thus preventing the cell from reaching the threshold of depolarization that unlocks nmda receptors from the mg block ( figure 1b ) . all in all , our experiments indicate that gr affect ltp through a fast , probably non - genomic mechanism . even though this hypothesis needs to be explored further , the fast suppression of ltp in the dh can underlie the switch in the weight between the dh and vh ; by reducing dh ltp and simultaneously enhancing ltp in the vh , the stressful stimuli could temporarily suppress the cognitive route of the hippocampus to cortical structures and enable the transmission of the emotional information through the vh to the amygdala . conversely , ltd induction is facilitated by behavioral stress , through a mechanism that requires gr ( pavlides et al . we replicated previous experiments where both stress and corticosterone facilitate ltd through a gr - dependent mechanism in the dh , but we have also shown that ltd is impaired in the vh through a mr - dependent mechanism ( maggio and segal , 2009b ) . specifically in the latter case , ltd is transformed into a slow - onset ltp following the exposure to stressful stimulation ( maggio and segal , 2009b ) . as is the case for ltp , changes in ltd either in the dh or vh were observed at approximately 1 h after the exposure to the stress , a time window that could be compatible with non - genomic mechanisms . the mr - induced conversion of ltd to ltp in the vh could be due to the activation of vgcc , which will further facilitate the ventral route to the amygdale ( figure 1b ) . group i mglur have been shown to enhance ltd in ca1 ( fitzjohn et al.,2001 ; rammes et al . , 2003 ) , but , interestingly , they have been reported to induce a slow - onset potentiation in the dg ( manahan - vaughan and reymann , 1996 ) . in a previous study , we showed that , in the vh , application of dhpg , a group i mglur agonist , increases the population spike amplitude in response to a baseline stimulation ( maggio and segal , 2007a ) . taken together , these observations suggest that in the vh , a decrease in gabaergic inhibition can shift ltd to a slow - onset ltp through a group i mglur - mediated mechanism ( figure 1b ) . in conclusion , corticosteroid regulation of synaptic plasticity in the hippocampus is affected by several factors . an inverted u - shape effect of corticosterone partially explains the observed modulation of ltp . indeed , this hypothesis mainly refers to the activation of intracellular corticosteroid receptors and does not take into account the contribution of membrane - bound steroid receptors . in fact , mmr , which bears a similar corticosterone affinity to that of igr , will be activated at similar steroid concentrations . this implies that the effect of mmr appears earlier than that of igr , thus inducing an enhancement of ltp instead of ltd an additional factor to be considered is the distribution of mr and gr in specific brain areas , and the ratio of membrane - bound to intracellular receptors expressed therein . this is because at the same affinity value for corticosterone concentration , the receptor that is highly expressed will lead the effects on synaptic plasticity . mrs , for example , exist in different molecular configurations ( joels , 2008 ) , thus these receptors can be very diverse . this diversity in molecular structure could be linked to diverse intracellular pathways that differently influence neuronal functions . another issue that has to be considered is the clusters of brain areas that are involved in a particular stress situation . various brain regions have specific properties and are incorporated into unique networks , so that even if corticosterone evokes the same effect at the single cell level , this would not always result in the same effect on network functions such as ltp . for instance , both ca1 pyramidal neurons and granule cells in the dg highly express mr as well as gr ( joels , 2008 ) . in the dh , corticosterone and stress consistently suppress the induction of ca1 ltp in vivo and in vitro , unlike the case for the dg . tail shocks ( shors and dryver , 1994 ) can indeed suppress ltp ; however , in other situations , either no effect ( bramham et al . , 1998 ; gerges et al . , 2001 ; alfarez et al . , 2003 ) or enhancement of ltp has been reported ( kavushansky et al . , 2006 ) . this is because ltp in the dg seems to be more dependent on indirect inputs from the amygdale ( akirav and richter - levin , 2002 ; kavushansky and richter - levin , 2006 ) . finally , the response to a stressor is also determined by the history of the organism . for instance , the induction of ltp is impaired in animals that have been exposed to repetitive stress in the weeks prior to the experiment , even if corticosterone levels , at the time of ltp induction , are compatible with the expression of a normal ltp ( alfarez et al . , 2003 ) . studies on the effect of maternal care on synaptic plasticity report that animals that received very little maternal care have poor ltp when they are adult , as opposed to animals that received high maternal care ( champagne et al . , 2008 ) . interestingly , while ltp is suppressed by corticosterone in the latter group , it is enhanced in the former ( champagne et al . , 2008 ) . all in all , corticosteroid modulation of synaptic plasticity in the hippocampus seems to be more complex than previously thought and additional experiments are needed to address the role of membrane - bound as well as intracellular receptors on ltp / ltd regulation . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .