Astrocytic deletion of protein kinase R‐like ER kinase (PERK) does not affect learning and memory in aged mice but worsens outcome from experimental stroke

Abstract

Aging is associated with cognitive decline and is the main risk factor for a myriad of conditions including neurodegeneration and stroke. Concomitant with aging is the progressive accumulation of misfolded proteins and loss of proteostasis. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and activation of the unfolded protein response (UPR). The UPR is mediated, in part, by the eukaryotic initiation factor 2α (eIF2α) kinase protein kinase R‐like ER kinase (PERK). Phosphorylation of eIF2α reduces protein translation as an adaptive mechanism but this also opposes synaptic plasticity. PERK, and other eIF2α kinases, have been widely studied in neurons where they modulate both cognitive function and response to injury. The impact of astrocytic PERK signaling in cognitive processes was previously unknown. To examine this, we deleted PERK from astrocytes (AstroPERKKO) and examined the impact on cognitive functions in middle‐aged and old mice of both sexes. Additionally, we tested the outcome following experimental stroke using the transient middle cerebral artery occlusion (MCAO) model. Tests of short‐term and long‐term learning and memory as well as of cognitive flexibility in middle‐aged and old mice revealed that astrocytic PERK does not regulate these processes. Following MCAO, AstroPERKKO had increased morbidity and mortality. Collectively, our data demonstrate that astrocytic PERK has limited impact on cognitive function and has a more prominent role in the response to neural injury.

Therapeutic Potential of Targeting the PERK Signaling Pathway in Ischemic Stroke

“…The underlying reasons for this discrepancy remain unknown. However, strong evidence obtained from genetic modulation of the PERK/p-eIF2α pathway supports the notion that activation of this pathway improves acute outcome after ischemic stroke [21,64]. Notably, no study has yet attempted to specifically dissect the role of the PERK pathway in stroke recovery during the chronic phase.…”

“…Two studies have used conditional PERK knockout mouse models in stroke research, and both support the notion that activation of the PERK branch during the acute phase is brain protective in stroke [ 21 , 64 ].…”

“…Our data indicated that deletion of Perk in neurons reduced p-eIF2α levels in the brain, and significantly worsened the neurologic outcomes after stroke [ 21 ]. In a more recent study, the authors crossbred Perk f/f mice with GFAP-Cre mice, and generated PERK-cKO Astrocyte mice [ 64 ]. They found that deletion of Perk in astrocytes increased morbidity and mortality after stroke.…”

“…Moreover, since mounting evidence indicates that the PERK pathway is involved in cognitive functions (detailed below), they performed a battery of behavioral tests. However, they did not find any significant effect on learning, memory, or cognition in middle-aged and old PERK-cKO Astrocyte mice [ 64 ]. These findings demonstrate that astrocytic PERK exerts a minimal influence on cognitive function, but plays a protective role in responding to neural injury.…”