Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer's Disease

Alberto Llorente-Ovejero, Iván Manuel, Laura Lombardero, Maria Teresa Giralt, Catherine Ledent, Lydia Giménez-Llort, Rafael Rodríguez-Puertas

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)


© 2018 - IOS Press and the authors. All rights reserved. The endocannabinoid system, which modulates emotional learning and memory through CB 1 receptors, has been found to be deregulated in Alzheimer's disease (AD). AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus. Neurochemical correlates were simultaneously studied with both receptor and functional autoradiography for CB 1 and muscarinic receptors, and regulations at the cellular level were depicted by immunofluorescence. 3xTg-AD mice exhibited increased acquisition latencies and impaired memory retention compared to age-matched non-transgenic mice. Neurochemical analyses showed changes in CB 1 receptor density and functional coupling of CB 1 and muscarinic receptors to G i/o proteins in several brain areas, highlighting that observed in the basolateral amygdala. The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB 1 receptor downregulation and CB 1 -mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes. A CB 1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB 1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.
Original languageEnglish
Pages (from-to)117-136
JournalJournal of Alzheimer's Disease
Issue number1
Publication statusPublished - 1 Jan 2018


  • 3xTg-AD
  • Alzheimer's disease
  • autoradiography
  • basolateral amygdala
  • cholinergic
  • endocannabinoid
  • learning and memory


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