Cell-type specific CB1 receptor modulation of hippocampal synaptic plasticity and memory

Abstract

The endocannabinoid system is a major brain modulatory system that controls memory and learning mainly via the cannabinoid receptor type 1 (CB1)-dependent regulation of neuronal and glial activity. In the hippocampus, bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. CB1 receptors have been shown to be present in the astrocytes and to mediate the disruptive effects of cannabinoids in synaptic plasticity and working memory. Yet, it is not currently known the role of this receptor in the physiological modulation of memory processes. Also, previous studies have shown that CB1 receptors expressed in dopamine D1 receptor-expressing cells are involved in the modulation of hippocampal-dependent aversive memories. However, their involvement in the modulation of non-aversive long-term memory formation and synaptic plasticity is presently unknown. In this thesis, I aimed at identifying the cellular and molecular mechanisms by which specific CB1 receptors in distinct brain neuronal and glial populations contribute to the physiological modulation of synaptic plasticity and learning and memory. For this aim we used conditional genetic mutant mice lacking CB1 receptors specifically in astrocytes or in D1-positive cells. By coupling these genetic mouse models with behavioral, pharmacological, and in vitro and in vivo electrophysiological approaches, we dissected the role of these CB1 receptors in the formation of memory. First, we show that astroglial CB1 receptors in the hippocampus control long-term potentiation (LTP) of CA3-CA1 synaptic transmission and long-term recognition memory. By allowing physiological availability of D-serine at NMDA receptors via gliotransmission, astrocytes are important elements controlling glia-neuron interactions that underlie synaptic plasticity and memory functions. The data show that astroglial CB1 receptors control plasticity and memory by regulating the synaptic availability of D-serine at NMDA receptors. Second, we show that CB1 receptors D1-positive cells control the consolidation, but not acquisition, of new memories and the enhancement of LTP induced by learning, showing that specific subpopulations CB1 receptor-expressing cells differentially modulate these processes. Overall, by showing that the endocannabinoid system in astrocytes is an important modulator of learning and memory and by suggesting that CB1 receptors in D1-positive cells are important for specific components of memory formation, we provide functional evidence for the complex cell type-dependent regulation of long-term recognition memory by the CB1 receptors.