Postnatal development and adult function of the central nervous system are dependent on the capacity of neurons to effect long-term changes of specific properties in response to neural activity. This neuronal response has been demonstrated to be tightly correlated with the expression of a set of regulatory genes which include transcription factors as well as molecules that can directly modify cellular signaling. It is hypothesized that these proteins play a role in activitydependent responses. Previously, we described the expression and regulation in brain of an inducible form of prostaglandin synthase/cyclooxygenase, termed COX-2. COX-2 is a ratelimiting enzyme in prostanoid synthesis and its expression is rapidly regulated in developing and adult forebrain by physiological synaptic activity. Here we demonstrate that COX-2 immunoreactivity is selectively expressed in a subpopulation of excitatory neurons in neo-and allocortices, hippocampus, and amygdala and is compartmentalized to dendritic arborizations. Moreover, COX-2 immunoreactivity is present in dendritic spines, which are specialized structures involved in synaptic signaling. The developmental profile of COX-2 expression in dendrites follows well known histogenetic gradients and coincides with the critical period for activitydependent synaptic remodeling. These results suggest that COX-2, and its diffusible prostanoid products, may play a role in postsynaptic signaling of excitatory neurons in cortex and associated structures.Neural activity results in specific structural and functional modifications of the cerebral cortex. This activity-dependent process is essential for achieving the appropriate synaptic relationships during development and for normal function of the mature cortex (1). Recent studies are beginning to identify molecular mechanisms underlying activity-dependent changes (2). There is abundant correlative evidence linking neural activity and transcription factor (TF) expression (3). Members of the Fos, Jun, and zinc finger TF families are naturally expressed at high levels in specific populations of cortical neurons and this expression is tightly regulated by synaptic activity (4, 5). Furthermore, these TFs are also rapidly and transiently induced in different paradigms of synaptic plasticity consistent with the notion that they regulate the expression of specific effector genes that underlie long-term plasticity (3).In addition to TFs, the initial genomic response to neural activity includes proteins that can directly modify cellular function. Among them is an inducible form of the enzyme prostaglandin synthase/cyclooxygenase, termed COX-2 (6-9). Cyclooxygenase is the first enzyme in the prostaglandin/ prostacyclin/thromboxane pathway and converts arachidonic acid to prostaglandin G2/prostaglandin H2. There are presently two known forms of cyclooxygenase: a constitutively expressed form termed COX-1 (10) and the inducible formThe publication costs of this article were defrayed in part by page charge payment. This article must the...

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE 2 . PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-␣ and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE 2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites. ( J. Clin. Invest. 1996. 97:2672-2679.)

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The formation of cloned bovine endothelial cells into capillary-like tubes is accelerated from 3-7 days to 2-18 h in the presence of fibrin. Indirect immunofluorescence showed the presence of both fibrin and fibronectin in the strands along which the cells organized. Electronmicroscopy revealed the same type of cell structures as form in the absence of fibrin; it also revealed a gradual decrease with time of the fibrin within the putative lumen. Fibrin and fibronectin are commonly present during angiogenesis in vivo, thus these in vitro observations may well have relevance to the in vivo process.

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