Corticotropin-Releasing Hormone Suppresses Synapse Formation in the Hippocampus of Male Rats via Inhibition of CXCL5 Secretion by Glia

Corticotropin-releasing hormone (CRH) is believed to play a critical role in stress-induced synaptic formation and modification. In the current study, we explored the mechanisms underlying CRH modulation of synaptic formation in the hippocampus by using various models in vitro. In cultured hippocampal slices, CRH treatment decreased synapsin I and postsynaptic density protein 95 (PSD95) levels via CRH receptor type 1 (CRHR1). In isolated hippocampal neurons, however, it increased synapsin I-labeled presynaptic terminals and PSD95-labeled postsynaptic terminals via CRHR1. Interestingly, the inhibitory effect of CRHon synapsin I-labeled and PSD95-labeled terminals occurred in the model of neuron-glia cocultures. These effects were prevented by CRHR1 antagonist. Moreover, treatment of the neurons with the media of CRH-treated glia led to a decrease in synaptic terminal formation. Themedia collected fromCRH-treated glial cells with CRHR1 knockdown did not show an inhibitory effect on synaptic terminals in hippocampal neurons. Unbiased cytokine array coupled with confirmatory enzyme-linked immunosorbent assay revealed that CRH suppressed C-X-C motif chemokine 5 (CXCL5) production in glia via CRHR1. Administration of CXCL5 reversed the inhibitory effects of CRH-treated glia culturemedia onsynaptic formation. Our data suggest that CRHsuppresses synapse formation through inhibition of CXCL5 secretion from glia in the hippocampus. Our study indicates that glia-neuron intercommunication is one of the mechanisms responsible for neuronal circuit remodeling during stress.