The hippocampal endocannabinoid system in different memory phases: Unveiling the CA1 circuitry

Abstract

CB1 Cannabinoid receptors are widely expressed throughout the brain, particularly in areas involved in learning and memory, such as the hippocampus. In the CA1 area, they are mainly present at the presynaptic terminals of both GABAergic and glutamatergic neurons. The antagonist/inverse agonist AM251 is a useful pharmacological tool due to its selectivity and ability to tap into the endocannabinoid system (ECS). When infused into the brain, it interferes with the natural functioning of the local pool of endocannabinoids present in each memory phase, and by suppressing the natural course of events, exposes its function in each situation. Anandamide (AEA) was also studied, but results were less consistent. In a large set of experiments spanning several years we have shown that different memory phases are modulated in opposite, complementary ways: AM251 was amnestic (and AEA, facilitatory) when infused into CA1 both after training (consolidation) or after a long reactivation session (extinction), suggesting that ECS modulates positively these phases. On the other hand, AM251 facilitated (and AEA frequently disrupted) memory before test (retrieval) or after a short reactivation session (reconsolidation), suggesting a negative modulatory role. Thus, simmetrically opposed actions are the rule for the ECS in the CA1 area, suggesting both plastic events and complex selective roles taking place under its control, e.g. "switching" between extinction and reconsolidation. Results were interpreted according to known CA1 circuitry and the most probable position of cannabinoid CB1 receptors, pointing to a complex, multifunctional modulatory system that is perfectly consistent with its ubiquity in mammal brains.