A CRHR1 antagonist prevents synaptic loss and memory deficits in a trauma-induced delirium-like syndrome

• Published in: Molecular psychiatry Vol. 26; no. 8; pp. 3778 - 3794
• Main Authors: Cursano, Silvia, Battaglia, Chiara R., Urrutia-Ruiz, Carolina, Grabrucker, Stefanie, Schön, Michael, Bockmann, Jürgen, Braumüller, Sonja, Radermacher, Peter, Roselli, Francesco, Huber-Lang, Markus, Boeckers, Tobias M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2021; Nature Publishing Group
• Subjects: 13/105; 13/51; 14/28; 631/378; 631/477; 64/60; 692/699/476/1414; 82/79; Age; Animals; Antipsychotic drugs; Autophagy; Behavioral Sciences; Biological Psychology; Brain-derived neurotrophic factor; Central nervous system; Clinical trials; Cognition; Complications and side effects; Corticotropin releasing hormone; Delirium; Development and progression; Dosage and administration; Drug therapy; Health aspects; Hippocampus; Hippocampus (Brain); Hormone receptors; Humans; Lysosomes; Medicine; Medicine & Public Health; Memory; Memory Disorders - drug therapy; Memory Disorders - etiology; Memory, Disorders of; Mice; Motor activity; Neurons; Neurosciences; NF-κB protein; Phagocytosis; Pharmacotherapy; Physiological aspects; Prevention; Psychiatry; Pyramidal cells; Receptors, Corticotropin-Releasing Hormone; Risk factors; Synapses; Syndrome; Thorax; Trauma; Wounds and injuries; Germany
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-020-0659-y

Older patients with severe physical trauma are at high risk of developing neuropsychiatric syndromes with global impairment of cognition, attention, and consciousness. We employed a thoracic trauma (TxT) mouse model and thoroughly analyzed age-dependent spatial and temporal posttraumatic alterations in the central nervous system. Up to 5 days after trauma, we observed a transient 50% decrease in the number of excitatory synapses specifically in hippocampal pyramidal neurons accompanied by alterations in attention and motor activity and disruption of contextual memory consolidation. In parallel, hippocampal corticotropin-releasing hormone (CRH) expression was highly upregulated, and brain-derived neurotrophic factor (BDNF) levels were significantly reduced. In vitro experiments revealed that CRH application induced neuronal autophagy with rapid lysosomal degradation of BDNF via the NF-κB pathway. The subsequent synaptic loss was rescued by BDNF as well as by specific NF-κB and CRH receptor 1 (CRHR1) antagonists. In vivo, the chronic application of a CRHR1 antagonist after TxT resulted in reversal of the observed histological, molecular, and behavioral alterations. The data suggest that neuropsychiatric syndromes (i.e., delirium) after peripheral trauma might be at least in part due to the activation of the hippocampal CRH/NF-κB/BDNF pathway, which results in a dramatic loss of synaptic contacts. The successful rescue by stress hormone receptor antagonists should encourage clinical trials focusing on trauma-induced delirium and/or other posttraumatic syndromes.