Chronic suppression of monoacylglycerol lipase restores adult neurogenesis in the septal but not the temporal DG in Ts65Dn mouse model of Down syndrome.

Donya Fozoonmayeh, Mathangi Sankaran, Jessica Yu, Meriel Walsh, Anna Tyrtyshnaia, Alexander M Kleschevnikov

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Article in Brain research bulletin, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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6 authors.

Donya FozoonmayehDepartment of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Mathangi SankaranDepartment of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Jessica YuDepartment of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Meriel WalshDepartment of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Anna TyrtyshnaiaDepartment of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Alexander M KleschevnikovDepartment of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: akleschevnikov@ucsd.edu.

Funding

Preventing cognitive impairment in mouse genetic models of Down syndrome by early postnatal suppression of Kir3.2 channel signalingR01HD100607 · NICHD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KLESCHEVNIKOV, ALEXANDER M · 2020 to 2024

$2.0M

NICHD NIH HHS R01 HD100607

6 · The paper itself

Abstract

Down syndrome (DS) is a genetic disorder characterized by cognitive impairment and varying degrees of changes in emotion-related behaviors. A deficiency in adult hippocampal neurogenesis is among the cellular mechanisms implicated in both abnormalities. Previously, we observed that chronic inhibition of monoacylglycerol lipase (MAGL) with the selective inhibitor JZL184 increased brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), improved hippocampal synaptic plasticity and long-term memory, but did not affect anxiety-related thigmotactic behavior in Ts65Dn mice, a genetic model of DS. In this study, we tested the hypothesis that these effects of JZL184 might be associated with changes in adult hippocampal neurogenesis. Ts65Dn mice and their normosomic (2 N) littermates were injected daily for 3 weeks with JZL184 or vehicle, and bromodeoxyuridine (BrdU) was co-administered during the chronic phase of the treatment. BrdU-immunopositive cells were quantified in the septal, medial, and temporal segments of the dentate gyrus (DG). It was observed that both the total number and the density of BrdU-positive cells were significantly reduced in Ts65Dn mice compared to their 2 N littermate controls. Strikingly, JZL184 treatment effects exhibited a profound septo-temporal bias: the BrdU-immunopositive cell density was restored to near control levels in the septal DG (a region presumably linked to cognitive function), but it was largely unaffected in the temporal DG (presumably associated with emotion-related behaviors). These results suggest that chronic MAGL inhibition may provide a targeted region-specific therapeutic strategy for cognitive impairment in Down syndrome, potentially independent of its effects on emotional behavior.

Indexed as

Down SyndromeMonoacylglycerol LipasesNeurogenesisAnimalsBenzodioxolesBromodeoxyuridineDentate GyrusDisease Models, AnimalEnzyme InhibitorsHippocampusMaleMiceMice, Inbred C57BLMice, TransgenicPiperidinesPropanolaminesBenzodioxolesBromodeoxyuridineEnzyme InhibitorsJZL 184Monoacylglycerol LipasesPiperidinesPropanolamines2-Arachidonoil glycerolAdult neurogenesisDentate gyrusEndocannabinoid systemGenetic modelsJZL184Monoacylglycerol lipaseSeptalTemporal

Identifiers

PMID41519177

DOI10.1016/j.brainresbull.2026.111721

PMCPMC13387813

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.