The effects of stress and corticosterone on synaptic plasticity and neuronal morphology in the rodent hippocampus

Elevation of circulating corticosterone levels, either through exogenous administration of the hormone or following stress exposure, is known to reduce hippocampal synaptic potentiation in rodents. It is presently debated whether this reduction is due to activation of hippocampal glucocorticoid receptors or is primarily caused in other brain structures projecting to the hippocampus. To address this issue, we examined whether synaptic potentiation in hippocampal slices from mice with low basal corticosterone levels was altered 1-4 hrs after a brief in vitro administration of 100 nM corticosterone. Population spike and field EPSP were recorded in the cell and dendritic layers respectively of the CA1 area, in response to Schaffer-commissural fiber stimulation. Basal characteristics of the stimulus-response relationship were not affected by corticosterone treatment, except that after corticosterone treatment the maximal field EPSP slope was reduced while the excitability ratio was increased. For studies on potentiation of the field EPSP and population spike, stimulus intensities were chosen to evoke half maximal responses before potentiation; this intensity was significantly lower for the field EPSP than for the population spike. Primed burst potentiation of the field EPSP but not population spike was significantly attenuated after corticosterone treatment. When using a more rigorous stimulation paradigm, i.e. theta burst potentiation; synaptic potentiation was not affected by corticosterone. Raising corticosterone levels in mice by exposure to a psychosocial stressor led to comparable results in subsequent in vitro experiments; stress reduced primed burst potentiation only of the field EPSP. These data support that corticosterone affects synaptic potentiation in the mouse via direct activation of hippocampal glucocorticoid receptors but only when using mild stimulation conditions. Introduction Corticosteroid hormones are released from the adrenal glands in a circadian rhythm and elevated circulating levels are often found after exposure to stressful events (De Kloet, 1991). Due to their lipophilic character corticosteroids readily cross the blood-brain barrier and bind to both thus far characterized receptors in the brain: the mineralocorticoid-receptor (MR) and glucocorticoid-receptor (GR) which are enriched in the hippocampal formation (McEwen et al., 1986). Over the past decade, in vivo as well as in vitro recording of synaptic plasticity have demonstrated that elevation of of corticosteroid hormones or stress influence hippocampal synaptic plasticity. Diamond et al. (1992) demonstrated that in vivo elevated corticosteroid levels (presumably occupying both MR and GR) impair primed burst potentiation in the CA1 hippocampal area of the rat, while low levels of corticosterone (predominantly occupying MRs) facilitate primed burst potentiation (Diamond et al., 1992). The role of the two corticosteroid receptors was strengthened by subsequent experiments in which selective MRand GR-ligands were applied prior to induction of synaptic potentiation (Pavlides et al., 1995a). A similar involvement of the corticosteroid receptors was also proposed for other hippocampal subfields (Pavlides and McEwen, 1999; Pavlides et al., 1996; Pavlides et al., 1995b). Importantly, not only exogenously applied corticosterone but also endogenous release of the hormone due to stressful conditions was shown to suppress hippocampal long-term potentiation in vitro (Foy, 1987; Kim et al., 1996; Mesches et al., 1999; Shors et al., 1989) and in vivo (Diamond et al., 1994; Shors and Dryver, 1994; Smriga et al., 1996; Xu et al., 1997; Xu et al., 1998b). The suppressive effects mediated by the GR on synaptic potentiation were observed both after acute and prolonged elevation of corticosteroid levels (Bodnoff et al., 1995b; Domenici et al., 1996; Karten et al., 1999; Pavlides et al., 1993; Smriga et al., 1996). Although there seems to be general consensus on the finding that stress modulates hippocampal synaptic plasticity, it is much debated whether this modulation is primarily caused by effects of corticosterone via hippocampal MRs and GRs. Thus, recent studies have shown that in vivo the amygdalar complex is critical for the development of stress-induced effects on hippocampal synaptic plasticity (Akirav, 1999; Kim, 2001). This may imply that stress-induced activation of amygdala rather than hippocampal GRs is 29 THESIS_DEB 07-02-2006 09:35 Pagina 29