NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH.

The complex effects of stress on learning and memory are mediated, in part, by stress-induced changes in the composition and structure of excitatory synapses. In the hippocampus, the effects of stress involve several factors including glucocorticoids and the stress-released neuropeptide corticotropin-releasing hormone (CRH), which influence the integrity of dendritic spines and the structure and function of the excitatory synapses they carry. CRH, at nanomolar, presumed-stress levels, rapidly abolishes short-term synaptic plasticity and destroys dendritic spines, yet the mechanisms for these effects are not fully understood. Here we tested the hypothesis that glutamate receptor-mediated processes, which shape synaptic structure and function, are engaged by CRH and contribute to spine destabilization. In cultured rat hippocampal neurons, CRH application reduced dendritic spine density in a time- and dose-dependent manner, and this action depended on the CRH receptor type 1. CRH-mediated spine loss required network activity and the activation of NMDA, but not of AMPA receptors; indeed GluR1-containing dendritic spines were resistant to CRH. Downstream of NMDA receptors, the calcium-dependent enzyme, calpain, was recruited, resulting in the breakdown of spine actin-interacting proteins including spectrin. Pharmacological approaches demonstrated that calpain recruitment contributed critically to CRH-induced spine loss. In conclusion, the stress hormone CRH co-opts mechanisms that contribute to the plasticity and integrity of excitatory synapses, leading to selective loss of dendritic spines. This spine loss might function as an adaptive mechanism preventing the consequences of adverse memories associated with severe stress.