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.

Delirium

“…Of note, the hypothalamic-pituitary axis is usually activated in tandem with the sympathetic nervous system and increased cortisol has been associated with delirium in a number of settings. Interestingly, cognitive deficits associated with thoracic trauma in mice are blocked with a corticotropin-releasing hormone receptor 1 (CRHR1) antagonist, which prevents cortisol release 171 .…”

Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons

“…Before termination of anesthesia, buprenorphine (0.03 mg per kg body weight) was injected subcutaneously to provide suitable analgesia. TxT was induced by a single blast wave centered on the thorax as previously described by Cursano et al 32 . One control group (Sham) of animals were subjected to the same experimental procedure, without TxT.…”

“…Since CRH triggers a dramatic loss of synapses 32 , which require high amount of energy (ATP) 48 , we investigated the effect of CRH release on neuronal mitochondria by analysing their morphology in mice 5 days after trauma (5 TxT) ( Fig. 2A).…”

“…To confirm that the mitochondrial aberrations occurring after peripheral trauma were specifically induced by CRH release (as in the case of synaptic loss; Cursano et al 32 ) we exposed primary hippocampal neurons ( Fig. Suppl.…”

“…Our group has described a dramatic (but reversible) CRH-dependent loss of hippocampal synapses and cognition impairment (in absence of neuronal death) after blunt thorax trauma (TxT) 32 , which opened the question whether mitochondria might also be directly involved in the maladaptive alterations triggered by the activation of the CRH receptor 1 (CRHR1). To answer this, we investigated the effect of CRH on mitochondrial dynamics, structural organization and functionality in hippocampal neurons.…”