Changes of Properties of Glutamatergic Synapses in the Hippocampus of Rats with Behavioral Depression and Modeling of the Changes in vitro

Abstract

Stress-induced (72-h-long social isolation-evoked) behavioral depression in rats was shown to be accompanied by a significant moderation of long-term potentiation (LTP) and a concurrent intensification of long-term depression (LTD) and depotentiation of synaptic transmission in the hippocampal CA1 region. Such changes of the properties of glutamatergic synapses in the hippocampus can be modeled by 1-h-long application of a synthetic glucocorticoid (GC), prednisolone (1 μM), to hippocampal slices from intact rats. In this case, two-phase changes in the efficiency of synaptic transmission in the CA1 are observed: depression is followed by short facilitation. Prednisolone-determined changes in synaptic transmission in the CA1 region are of a presynaptic nature. Facilitation of prednisolone-evoked transmission could be reproduced by application of a synthetic GC, dexamethasone (100 nM, 10 min), which possesses no mineralocorticoid activity. The GC-elicited reversible intensification of synaptic transmission in the CA1 region was prevented by polymixin B (50 μM). Short-term influence of GC did not prevent the development of LTP. Prednisolone-induced changes in synaptic plasticity phenomena occurring in the CA1 region were prevented by a blocker of NMDA receptors, D-2-amino-5-phosphonovaleric acid (50 μM), but not by a blocker of AMPA receptors, 6,7-dinitroquinoxaline-2,3-dione (10 μM). Such modifications were moderated by inhibitors of calmodulin (trifluoperazine, 5 μM) and protein kinase C (polymixin B, 50 μM), but did not change under the influence of an inhibitor of calcineurin (cyclosporin A, 50 μM). It is supposed that an in vivo stress-induced rise in the GC level and an in vitro application of GC primarily intensify presynaptic release of glutamate, which activate postsynaptic high-affinity NMDA receptors. Activation of NMDA receptors facilitates both binding of type-II GC receptors in the cytoplasm of pyramidal neurons with the hormone and translocation of these receptors into the nucleus of these cells with subsequent suppression of transcription of neurotrophins. Inhibition of release of the latter underlies the GC-induced suppression of LTP and, at the same time, intensifies LTD and depotentiation of synaptic transmission in the CA1 region.