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...