Urocortin 2 But Not Urocortin 3 Promotes the Synaptic Formation in Hipppocampal Neurons via Induction of NGF Production by Astrocytes.

CRH family peptides play differential role during various physiological and pathophysiological responses, such as stress. Urocortins (UCNs) have been implicated to play complementary or contrasting actions for the effects of CRH during stress. It has been shown that activation of CRH receptor type 1 (CRHR1) results in decreased synapse formation in hippocampus. We therefore explored the effect of UCN2 and UCN3, the exclusive CRHR2 agonists, on synaptic formation in hippocampus. In hippocampal slices cultures, UCN2 but not UCN3 treatment increased the levels of presynaptic protein synapsinI and postsynaptic protein postsynaptic density 95 (PSD95), which was reversed by CRHR2 antagonist astressin 2B. In isolated hippocampal neurons, however, UCN2 decreased the numbers of synapsinI- and PSD95-labeled terminals/clusters via CRHR2. Treatment of hippocampal neurons with the media of UCN2-treated astrocytes led to an increase in synapsinI- and PSD95-labeled terminals. In neuron-astrocyte cocultures, UCN2 also enhanced the numbers and level of synapsinI- and PSD95-labeled terminals. These effects did not occur if glial cells were transfected with CRHR2 small interfering RNA. UCN2 but not UCN3 treatment induced nerve growth factor (NGF) production in astrocytes via CRHR2. The effects of the media of UCN2-treated glial cells on synapse formation in hippocampal neurons were prevented by administration of NGF receptor antagonists. Our data indicate that UCN2 promotes synapse formation in hippocampus via induction of NGF secretion from astrocytes. CRHR2 in glial cells mediates the stimulatory effects of CRH. Glia-neuron communication is critical for neuronal circuits remodeling and synaptic plasticity in response to neurohormones or neuromodulators.