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

Abstract

The endocannabinoid system, which modulates emotional learning and memory through CB1 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 CB1 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 CB1 receptor density and functional coupling of CB1 and muscarinic receptors to Gi/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 CB1 receptor downregulation and CB1-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 CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

“…HU 210 ameliorated the memory deficits of olfactory bulbectomized (OBX) rats [ 114 ]. In contrast with what was previously reported, chronic treatment with WIN 55,212-2 significantly normalizes this cognitive deficit in old Tg APP mice accompanied by a reduction in the inflammation and an increased Aβ clearance [ 115 , 116 ]. Chronic administration of the selective CB1 agonist ACEA at pre-symptomatic or early AD stages reduced the learning and memory deficits observed in the double APP/PS1 transgenic mice.…”

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

“…Previous reports have demonstrated that sub-chronic administration of JZL184, an irreversible inhibitor of the MAGL, promotes downregulation and G-protein uncoupling of CB1R (22,23). We found that administration of JZL184 (8 mg/kg, i.p.)…”

CB1 and LPA1 Receptors Relationship in the Mouse Central Nervous System

“…The reported compensation would affect receptors coupled to other types of G proteins, however, as previously mentioned, we were only able to analyze those coupled to the G i/o subtype. It is improbable that CB 1 receptors play a role since previous results reported a similar distribution regarding the CB 1 receptor autoradiographic densities compared to functional autoradiography stimulated by specific agonists such as the WIN55212-2 (Llorente-Ovejero et al, 2018). However, it has not been yet possible to get the distribution of LPA 1 receptors.…”