T. Young, B. S. McEwen, unpublished data), providing further evidence that CRS-induced structural plasticity and the molecular markers Glt-1 and phosphoCREB arc useful in study of psychiatric illnesses. Structural changes in dendrites and spine synapses are the result of modifications in the microtubule system of the cytoskeleton,65 and new evidence shows that posttranslational modification of tubulin65 and phosphorylation of the microtubule associated protein tau66 take place along with changes in the actin cytoskeleton,67 under conditions in which reorganization of dendrites and synaptic connections

occur. Overall, cytoskeletal changes, such as increased paired-helical-like phosphorylation of tau66 and reduced tyrosinated Inhibitors,research,lifescience,medical tubulin,65 are consistent with increased cytoskeletal rigidity. However, this needs much careful study. The Rac/Rho guanosine triphosphatases (GTPases)

and related Inhibitors,research,lifescience,medical proteins such as the guanosine triphosphate (GTP) exchange factor, kalirin, have been shown to play a key regulatory role in cytoskeletal modifications in developing and adult neurons.67,68 Except for one relevant study on seizures,65 there are no studies thus far of the effects of chronic stress on these pathways or of the modifications of the cytoskeleton itself. Besides glucocorticoids and excitatory amino acids, neurotrophins and gp130 cytokines Inhibitors,research,lifescience,medical are implicated in structural plasticity along with extracellular proteases such as tissue plasminogen activator (tPA) and neuropsin. Brainderived Inhibitors,research,lifescience,medical neurotrophic factor (BDNF) plays a major role in activity-dependent

synaptic and dendritic remodeling,69-73 and is implicated in hippocampal-dependent memory formation.74 BDNF also regulates tPA release from neurons75 and tPA is released from nerve terminals in hippocampus and other brain areas such as amygdala.76-78 It has been suggested that tPA may play Inhibitors,research,lifescience,medical a role in the processing of proBDNF into active forms.79 The activity of tPA is associated with structural plasticity and increased fear,77 motor learning,80 and enhancement of AUY 922 long-term potentiation.81 Activity of tPA is an important mediator of structural plasticity and enhanced fear in the amygdala resulting from acute restraint stress. For example, plasminogen (inactive zymogen) leads to plasmin (active serine Rutecarpine protease). Using tPA knockout mice, we have found that in medial and central amygdala77: tPA is released under stress and initiates neural remodeling. This release is plasminogen-independent (extracellular signal–regulated kinase [ERK1/2]; guanosine triphosphate–activating protein [GAP-43]). tPA induces termination of its own action via plasminogen-activator inhibitor–1 (PAI-1). tPA activity is required for increased anxiety in the elevated plus maze. We are presently studying the long-term effects of stress. Neuropsin is another protease that is induced in hippocampus by NMDA-mediated excitation in seizures and leads to proteolysis of the presynaptic adhesion molecule, L1.