Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

Abstract

Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1 −/− ), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated agedependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1 −/− mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1 −/− mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.glial regulation | Morris water maze | stereological quantification | CD40 expression | telemetric EEG recording

The endocannabinoid system in normal and pathological brain ageing

“…In good agreement with these findings, genetic deletion of CB1 receptors leads to defective neurogenesis [221]. The consequence of this effect on the learning phenotype is unclear but it is unrelated to the early loss of cognitive abilities in this strain [197].…”

“…The peripheral organs also did not show signs of early ageing except in the skin, where an atrophy of the subdermal fat layer was present in 12-month-old CB1 2/2 but not in wild-type mice [5]. A following study showed that the early onset of cognitive decline and neuronal loss was accompanied by neuroinflammatory changes in the hippocampus, but not in the cortex or striatum [197]. It was suggested that CB1 receptors on the GABAergic neurons play a principal role in the regulation of glial activity and thus in protection against age-related changes: deletion of CB1 receptors from the forebrain GABAergic but not glutamatergic neurons resulted in a similar ageing phenotype as found in the constitutive knockouts [197].…”

“…A following study showed that the early onset of cognitive decline and neuronal loss was accompanied by neuroinflammatory changes in the hippocampus, but not in the cortex or striatum [197]. It was suggested that CB1 receptors on the GABAergic neurons play a principal role in the regulation of glial activity and thus in protection against age-related changes: deletion of CB1 receptors from the forebrain GABAergic but not glutamatergic neurons resulted in a similar ageing phenotype as found in the constitutive knockouts [197]. Interestingly, similar neuroinflammatory changes were not present in the cortex and striatum, brain areas having high expression of CB1 receptors and containing abundant GABAergic neurons.…”

Anti-inflammatory lipoxin A 4 is an endogenous allosteric enhancer of CB 1 cannabinoid receptor

“…Moreover, knowing that ajulemic acid induces the release of LXA 4 acting as a proresolving mediator in inflammation (30); that LXA 4 increases the affinity of AEA for the CB 1 receptors (this study); and that certain metabolites of AEA degradation by lipoxygenases retain affinity for the CB 1 receptor (46) or reduce AEA metabolism by FAAH (47), we may hypothesize that LOX derivatives such as LXA 4 might participate in a positive feedback loop sustaining endocannabinoid tonus under certain conditions, for example, brain inflammation (48), epilepsy (49,50), or aging (51). This may be an interesting explanation for the observed neuroprotection against β-amyloid (1-40)-induced memory impairment, which is regarded as an important component of Alzheimer's disease pathophysiology (52).…”

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

“…In fact, A␤ has been demonstrated to inhibit long-term plasticity processes associated with learning and memory through suppression of CB 1 -dependent GABAergic synaptic disinhibition [26]. Moreover, CB 1 receptor activity in GABAergic neurons protects against agedependent cognitive decline [27]. Therefore, it may be speculated that the combination of 9 -THC and CBD facilitates inhibitory GABAergic activity in the somatosensory cortex by mitigating the deleterious effect of A␤ on GABAergic function, and subsequently on cognitive performance, via activation of CB 1 receptors.…”