Cellular Mechanisms of Stress Induced Structural Plasticity

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Chronic or severe stress is a well-known precipitant of some forms of anxiety and depressive disorders, and it is likely that stress-induced alterations in neuronal plasticity may underlie functional changes. Stress exposure in experimental animals can result in dendritic remodeling and atrophy in hippocampal CA3 pyramidal neurons (Margarinos et al. 1996; Sousa et al. 2000; Watanabe et al. 1992) as well as decreased hippocampal volume and neurogenesis (Czeh et al. 2001; Gould et al. 1997). These findings, along with observations of decreased hippocampal volume seen clinically in association with PTSD and depression (Bremner et al. 1995; Sheline et al. 1996), and the observation that clinically effective antidepressant treatments can reverse stress-induced changes in neuronal structure (Magarinos et al. 1999), have suggested the potential relevance of stress-induced structural alterations to affective disorders (Duman et al. 2000; Manji et al. 2001; Nestler et al. 2002).

As in the hippocampus, dendritic remodeling occurs in the amygdala in response to stress exposure (Vyas et al. 2002). However, unlike the hippocampus where dendritic atrophy occurs, the amygdala shows dendritic hypertrophy in response to chronic immobilization stress. Exposure to immobilization stress also results in heightened emotionality in animals. Little is known about the signaling pathways that underlie the actions of stress in the hippocampus or amygdala. McEwen and colleagues have reported that decreased hippocampal neurogenesis by stress is dependent on NMDA receptor activation (i.e., the decrease is blocked by pretreatment with a NMDA receptor antagonist), which suggests that it is Ca2+ dependent (McEwen 1999). However, it is also possible that this effect of NMDA occurs outside the hippocampus. Activation of the cAMP-CREB cascade has been shown to increase neurogenesis and dendritic arborization of hippocampal neurons (Nakagawa et al. 2002). A role for extracellular proteolysis in mediating such structural changes has been suggested, and the serine protease tissue-plasminogen activator (tPA) has been studied in learning and activity-dependent plasticity in the hippocampus (Huang et al. 1996; Madini et al. 1999). Extracellular proteolysis mediated by tPA may also be important in the stress-induced regulation of plasticity including dendritic remodeling in the amygdala (Pawlak et al. 2003). Increased tPA in the central and medial nuclei of the amygdala has been shown after acute restraint stress. Mice in which tPA has been knocked out (tPA~'~ mice) lack the stress-induced phosphorylation of ERK1/2 that is seen in wild-type mice, and stress-induced increases in GAP-43, which is a presynaptic protein used as a marker of axonal plasticity, are also absent in tPA~'~ mice (Pawlak et al. 2003). Additionally, stress-induced increases in anxiety behavior do not occur in tPA-/- mice even though the hypothalamic-pituitary-adrenal (HPA) stress response of these mice is normal as assessed by corticosterone levels. These results suggest that tPA acts in the amygdala to facilitate stress-induced anxiety behavior and to promote cellular mechanisms of plasticity. The amygdala is thought to exert an excitatory drive on HPA axis function while the hippocampus inhibits the HPA axis (Allen and Allen 1974; Herman et al. 1989). It is suggested that the contrasting patterns of dendritic remodeling in response to stress in the amygdala and hippocampus could contribute to dysregulation of HPA axis function and comprise a candidate cellular substrate for behavioral consequences of chronic stress exposure.

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