Chronic social isolation is related to both upregulation of plasticity genes and initiation of proapoptotic signaling in Wistar rat hippocampus

Successful adaptation to stress involves actions of glucocorticoid receptor (GR), a steroid-dependent transcription factor, abundant in hippocampus. Another transcription factor, nuclear factor kappa B (NFκB) is considered as an important stress sensor implicated in adaptive synaptic plasticity. Numerous stress-related genes are regulated by both hippocampal GR and NFκB, including neural cell adhesion molecules (NCAM and L1), involved in plasticity, and genes that encode apoptotic proteins (bax and bcl-2). We presumed that the ratio of nuclear NFκB to nuclear GR may determine the degree of proplastic or proapoptotic signaling under stress. To test this presumption we have investigated effects of acute, chronic and combined stress on compartmental levels and ratios of NFκB and GR proteins, and in parallel, changes in their mRNA expression. In addition, the expression of plasticity (NCAM, L1) and apoptotic (bax, bcl-2) genes, as well as, Bax and Bcl-2 proteins redistribution between mitochondrial and cytoplasmic compartments, were followed. When glucocorticoid levels were low, as found in chronic stress, GR was not efficiently translocated to the nucleus. This resulted in its lower nuclear level relative to the nuclear NFκB. Such conditions did not affect proplastic induction of NCAM mRNA, but were related to the onset of proapoptotic signaling illustrated by relocation of mitochondrial Bcl-2 protein to its soluble cytoplasmic form. Because these Bcl-2 rearrangements were not reversed by subsequent acute stress, representing more stable alterations, it is concluded that chronic social isolation of Wistar rats led to the initiation of proapoptotic signaling that may be etiologically related to compromised adaptive response of central nervous system.