Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator

BACKGROUND: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI). METHODS: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention. FINDINGS: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window. INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI. FUNDING: 10.13039/501100004063Knut and Alice Wallenberg Foundation [F 2015/2112]; 10.13039/501100004359Swedish Research Council [VR; 2017-01243]; the 10.13039/501100001659German Research Foundation [DFG; ME 4667/2-1]; 10.13039/501100003792Hjärnfonden [FO2021-0112]; 10.13039/100018740The Crafoord Foundation; 10.13039/100007435Åke Wibergs Stiftelse [M19-0380], NMMP 2021 [V2021-2102]; the 10.13039/501100006189Albert Påhlsson Research Foundation; 10.13039/501100001728STINT [MG19-8469], 10.13039/501100003252Lund University; 10.13039/501100000024Canadian Institutes of Health Research [PJT-153269] and a 10.13039/100004411Heart and Stroke Foundation of Ontario Mid-Career Investigator Award.