Hsp60 deletion in cholinergic neurons: Impact on neuroinflammation and memory

Abstract

Cholinergic circuit defects have been linked to various neurological abnormalities, yet the precise mechanisms underlying the impact of cholinergic signaling on cognitive functions, particularly in the context of neuroinflammation-associated, remain poorly understood. Similarly, while the dopamine receptor (D2R) has been implicated in the pausing of cholinergic interneurons (CIN), its relationship with behavior remains inadequately elucidated. In this study, we aimed to investigate whether D2R plays a role in the regulation of fear and memory in the Hsp60 knockout condition, given the non-canonical involvement of Hsp60 in inflammation. Using a CRE-floxed system, we selectively generated cholinergic neurons specific to Hsp60 knockout mice and subjected them to memory tests. Our results revealed a significant increase in freezing levels during recall and contextual tests in Hsp60-deprived mice. We also observed dysregulation of neurotransmitters and D2R in the hippocampus of Hsp60 knockout mice, along with enhanced impairments in cytokine levels and synaptic protein dysregulations. These changes were accompanied by alterations in PI3K/eIF4E/Jak/ERK/CREB signaling pathways. Notably, D2R agonism via Quinpirole led to a decrease in freezing levels during recall and contextual tests, alongside an increase in IBA-1 expression and improvements in inflammatory response-linked signaling pathways, including JAK/STAT/P38/JNK impairments. Given that these pathways are well-known downstream signaling cascades of D2R, our findings suggest that D2R signaling may contribute to the neuroinflammation induced by Hsp60 deprivation, potentially exacerbating memory impairments.