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

Abstract:

: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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Cursano S,Battaglia CR,Urrutia-Ruiz C,Grabrucker S,Schön M,Bockmann J,Braumüller S,Radermacher P,Roselli F,Huber-Lang M,Boeckers TM

doi

10.1038/s41380-020-0659-y

subject

Has Abstract

pub_date

2020-02-12 00:00:00

eissn

1359-4184

issn

1476-5578

pii

10.1038/s41380-020-0659-y

pub_type

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