Stress vulnerability induced by neonatal isolation and the disturbance between the phosphorylation and dephosphorylation of CREB

Abstract

Lifetime prevalence of posttraumatic stress disorder (PTSD) has been found torange from 1.0% to 12.3% based on general-population and service-sector samples(Fairbank et al. 1995), which demonstrates that not all victims suffer from PTSD. Itis conceivable that individual differences in stress reactivity may play a role in thedevelopment of PTSD. In addition, traumatization in early development, e.g., physicalabuse or separation from parents, has been shown to be associated with the developmentof PTSD (Fairbank et al. 1995; Bremner et al. 1999; Pine and Cohen2002).Various animal studies indicate that early adverse experiences change stress reactivityin adult rats (Kaufman et al. 2000). Neonatal isolation as well as maternalseparation affects the response of the hypothalamo-pituitary-adrenal (HPA) axis toacute stress in adult rats (Francis et al. 1999; Ladd et al. 1996; Plotsky and Meaney1993). Furthermore, neonatal isolation induces an increase in the central noradrenalinedrive and reduction in the activity of the inhibitory central GABA/BZ system inadulthood (Caldji et al. 2000; Liu et al. 2000).Recent molecular pharmacological studies have revealed that while glucocorti- coids regulate neuronal gene expression through their intracellular receptors, neurotransmittersalso modulate neuronal gene expression via the activation of proteinkinases and transcription factors. Whereas homeostasis of the HPA axis and theneurotransmitter systems are maintained in adult rats that have been subjected toneonatal isolation, under a low-stress environment, it is plausible that an exposureto stress in adulthood may easily lead to alterations in neuronal gene expressionthrough changes in the activity of transcription factors. Subsequently, stress vulnerabilitymay become evident. Therefore, examining the influence of neonatal isolationon the phosphorylation and dephosphorylation of transcription factors in theadult rat brain may contribute to the elucidation of the molecular mechanism underlyingstress vulnerability.In this chapter, we describe the possible molecular mechanism for the stress vulnerabilityinduced by neonatal isolation, based on the disturbance between the phosphorylationand dephosphorylation of cyclic AMP-response element binding protein(CREB), a major transcription factor. At first, we start with a brief descriptionof neonatal isolation adopted in our study. Following this, we show the influence ofneonatal isolation on the phosphorylation of CREB and the activity of protein phosphatases,key enzymes for dephosphorylation of phospho-CREB as well as autophosphorylated-calcium/calmodulin-dependent (CaM) kinases, in the adult rat hippocampusin response to a single restraint stress in adulthood.