Abstract
Spatial recognition memory impairment is an important complication after traumatic brain injury (TBI). We previously found that spatial recognition memory impairment can be alleviated in adenosine A2A receptor knockout (A2AR KO) mice after TBI, but the mechanism remains unclear. In the current study, we used manganese‐enhanced magnetic resonance imaging and the Y‐maze test to determine whether the electrical activity of neurons in the retrosplenial cortex (RSC) was reduced and spatial recognition memory was impaired in wild‐type (WT) mice after moderate TBI. Furthermore, spatial recognition memory was damaged by optogenetically inhibiting the electrical activity of RSC neurons in WT mice. Additionally, the electrical activity of RSC neurons was significantly increased and spatial recognition memory impairment was reduced in A2AR KO mice after moderate TBI. Specific inhibition of A2AR in the ipsilateral RSC alleviated the impairment in spatial recognition memory in WT mice. In addition, A2AR KO improved autophagic flux in the ipsilateral RSC after injury. In primary cultured neurons, activation of A2AR reduced lysosomal‐associated membrane protein 1 and cathepsin D (CTSD) levels, increased phosphorylated protein kinase A and phosphorylated extracellular signal‐regulated kinase 2 levels, reduced transcription factor EB (TFEB) nuclear localization and impaired autophagic flux. These results suggest that the impairment of spatial recognition memory after TBI may be associated with impaired autophagic flux in the RSC and that A2AR activation may reduce lysosomal biogenesis through the PKA/ERK2/TFEB pathway to impair autophagic flux.
Highlights
| INTRODUCTIONSpatial recognition memory is a type of spatial memory that allows animals to recognize a new environment.[1,2] Traumatic brain injury (TBI) is one of the most common brain injuries; the impaired spatial memory caused by traumatic brain injury (TBI) severely reduces the survival of patients and poses a significant burden to their families and society.[3,4,5] a variety of methods have been used to alleviate this impairment, few effective and feasible treatments are available.[4,6,7] The adenosine A2A receptor (A2AR) is a type of G protein-coupled receptor that can be activated by markedly increased adenosine after TBI
We found that spatial recognition memory was significantly improved compared to that in the vehicle group, suggesting that A2A receptor (A2AR) activation in the ipsilateral retrosplenial cortex (RSC) is associated with spatial recognition memory impairment after moderate traumatic brain injury (TBI)
We found that spatial recognition memory was obviously impaired in CQ-treated WT mice compared to that in CQ-treated A2A receptor knockout (A2AR KO) mice, further indicating that the alleviation of spatial recognition memory impairment through the inhibition of A2AR in the ipsilateral RSC after TBI is related to improved autophagic flux in neurons and a reduction in apoptosis
Summary
Spatial recognition memory is a type of spatial memory that allows animals to recognize a new environment.[1,2] Traumatic brain injury (TBI) is one of the most common brain injuries; the impaired spatial memory caused by TBI severely reduces the survival of patients and poses a significant burden to their families and society.[3,4,5] a variety of methods have been used to alleviate this impairment, few effective and feasible treatments are available.[4,6,7] The adenosine A2A receptor (A2AR) is a type of G protein-coupled receptor that can be activated by markedly increased adenosine after TBI. Cell death has been reported as an important cause of spatial recognition memory impairment.[4,6,7] we previously found that improving autophagic flux is an important factor for reducing cell death in A2AR knockout (KO) mice after moderate TBI, which provides new support for the neuroprotective effects of A2AR.[11] we hypothesize that inhibiting A2AR activation to improve autophagic flux may be associated with improving spatial recognition memory impairment after TBI To answer these questions, we first used manganese-enhanced magnetic resonance imaging (MEMRI) to clearly identify the retrosplenial cortex (RSC) as the significantly changed region in wild-type (WT) mice after moderate TBI while A2AR KO mice could reverse this change. We explored the mechanism of impaired autophagic flux induced by A2AR in vivo and in vitro
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