Knockdown of adenosine A2A receptors in hippocampal neurons prevents post-TBI fear memory retrieval.

The formation of fear memory is crucial in emotional disorders such as PTSD and anxiety. Traumatic brain injury (TBI) can cause emotional disorders with dysregulated fear memory formation; however, their cross-interaction remains unclear and hurdled the treatment against TBI-related emotional disorders. While adenosine A2A receptor(A2AR) contributes to the physiological regulation of fear memory, this study aimed to evaluate the A2AR role and possible mechanisms in post-TBI fear memory formation using a craniocerebral trauma model, genetically modified A2AR mutant mice, and pharmacological A2AR agonist CGS21680 and antagonist ZM241385. Our finding showed (i) TBI enhanced mice freezing levels (fear memory) at seven days post-TBI; (ii) The A2AR agonist CGS21680 enhanced the post-TBI freezing levels; conversely, the A2AR antagonist ZM241385 reduced mice freezing level; further (iii) Genetic knockdown of neuronal A2AR in the hippocampal CA1, CA3, and DG regions reduced post-TBI freezing levels, while A2AR knockout in DG region yielded the most reduction in fear memory; finally, (iv) AAV-CaMKII-Cre virus-mediated DG deletion of A2AR on excitatory neurons led to a significant decreased freezing levels post-TBI. These findings indicate that brain trauma increases fear memory retrieval post-TBI, and A2AR on DG excitatory neurons plays a crucial role in this process. Importantly, inhibition of A2AR attenuates fear memory enhancement, which provides a new strategy to prevent fear memory formation/enhancement after TBI.

Ablation of GSDMD Attenuates Neurological Deficits and Neuropathological Alterations After Traumatic Brain Injury.

Pyroptosis plays a significant role in neuroinflammation after traumatic brain injury (TBI). However, the role of pyroptosis executor Gasdermin D (GSDMD) in neurological deficits and neuropathological alterations after TBI have not been elucidated. Our results demonstrated that GSDMD-KO exerted striking neuroprotective effects on motor dysfunction and neuropathological alterations (loss of synaptic proteins, microglia activation, astrogliosis, dendrite injury, and neuron death) at 3 days after TBI. GSDMD-KO inhibited the expression and release of pro-inflammatory cytokine releases (IL-1ß and TNF-α) while promoting those of anti-inflammatory cytokines (IL-10 and TGF-ß1). The temporal pattern of diverse inflammasome signals showed long-lasting elevations of NLRP3, caspase 1, and caspase 1 p20 after TBI, rather than NLRP1, NLRC4 or AIM2, similar to the change in GSDMD postinjury; and NLRP3-KO not only inhibited the expression and cleavage of GSDMD but also attenuated the loss of synaptic proteins and neurological deficits. Notably, RNA sequencing showed both GSDMD-KO and NLRP3-KO reversed the global expression of neuroinflammation- and neuropathology-related genes after TBI. Our findings proved that the inhibition of GSDMD exerts neuroprotective effects after TBI and is mainly driven by the NLRP3 inflammasome. GSDMD serves as a potent therapeutic target for the treatment of TBI.