Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice

Abstract

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here we showed that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a pro-apoptotic protein MAPL (Mitochondrial Anchored Protein Ligase) selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition, and hippocampus-dependent longterm memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.

MAPL loss dysregulates bile and liver metabolism in mice

“…However, evidence in mouse models and at least one patient indicates a primary role for ABCD3 in the transport of branched chain acyl‐CoAs and bile acid precursors di‐ and tri‐hydroxycholestanoyl‐CoA (D/THC‐CoA) (Ferdinandusse et al , 2015). Given the specificity of the proximity biotinylation of ABCD3, we chose to validate and interrogate the potential functional consequences of MAPL‐ABCD3 binding in our MAPL knockout (MAPL −/− ) mouse line (Doiron et al , 2017; Roque et al , 2023), focusing on liver as a primary organ of bile acid production.…”

“…Mitochondrial and peroxisomal anchored protein ligase has been implicated in the regulation of ER/mitochondrial contact sites, mitochondrial quality control and cell survival pathways (Prudent et al , 2015; Rojansky et al , 2016; Roque et al , 2023); therefore, it was possible that the ISR may be activated in other, non‐bile acid‐producing tissues as well. In addition to liver, we observed an increase in the phosphorylation of PERK in the stomach, but this was not accompanied by an increase in CHOP (Fig 6G).…”

“…Indeed, we previously described critical roles for MAPL and the SUMOylation of DRP1 in the process of apoptosis (Prudent et al , 2015), suggesting that some of the cancer phenotype may arise due to an inhibition of cell death. More recent studies utilized this MAPL KO mouse strain and demonstrated that loss of MAPL within parvalbumin interneurons protected against cell death and memory loss linked to postnatal anesthesia exposure (Roque et al , 2023). To test whether ectopic expression of MAPL may promote cell death directly, we infected a human liver cell line Huh7 with adenovirus coding for MAPL‐Flag, MAPL‐ΔRING‐Flag SUMOylation‐deficient mutant or the empty vector (Ad‐rtTA).…”

“…In addition, evidence in rodents has shown FGF21 as a negative regulator of bile acid synthesis (Chen et al, 2018), again consistent with FGF21 upregulation within MAPL À/À mice playing a potentially compensatory role to reduce bile acid synthesis. Mitochondrial and peroxisomal anchored protein ligase has been implicated in the regulation of ER/mitochondrial contact sites, mitochondrial quality control and cell survival pathways (Prudent et al, 2015;Rojansky et al, 2016;Roque et al, 2023); therefore, it was possible that the ISR may be activated in other, non-bile acidproducing tissues as well. In addition to liver, we observed an increase in the phosphorylation of PERK in the stomach, but this was not accompanied by an increase in CHOP (Fig 6G).…”

Long-term sevoflurane exposure relieves stress-enhanced fear learning and anxiety in PTSD mice

“…This salutary effect was dose-dependent, as a 2-h administration signi cantly improved SEFL only on the rst day post-treatment while the treatment effect of the 6-h administration lasted at least 7 days. This sustained effect is also critical because repeated administration of inhaled anesthetics can induce brain damage in mice and humans 19,20 . However, we only tested two dose regimens (2 h and 6 h at a minimum alveolar concentration of 1.0), so other dose regimens should be tested to identify the most suitable starting parameters for subsequent studies.…”