Ruolo del recettore CB1 cellulare e sub-cellulare in cellule D1-positive dell'Ippocampo nei Processi della Memoria

Via modulation of neuronal activity by cannabinoid receptor type-1 (CB1), the endocannabinoid system represents a major brain modulatory system controlling memory functions. On the other hand, several reports point out a crucial role of hippocampal dopamine signaling in the regulation of memory related processes. Furthermore, recent evidence suggests that hippocampal cells expressing dopamine receptors do also posses CB1 receptors. The work presented in this Thesis aims at establishing a functional connection between CB1 receptor and dopaminoceptive signaling in the regulation of hippocampal related memory processes with particular enfasis on the cellular and sub-cellular mechanisms involved. In the first part of the thesis we observed that a mouse line lacking CB1 in dopamine receptor type- 1 cells (D1-CB1-KO) displayed impaired long-term novel object recognition memory (NOR) and, interestingly, viral-mediated re-expression of CB1 in D1-positive cells in the hippocampus of D1-CB1- KO mice reversed the NOR impairment present in these mice. Furthermore, we pointed out execessive hippocampal GABAA receptor activation and impaired in vivo long-term potentiation (LTP) in the CA3-CA1 pathway as the main cellular mechanisms for memory impairment in D1-CB1- KO. Thus, we provided functional evidence for the involvement of a small subclass of type-1 cannabinoid receptor (CB1)-expressing hippocampal interneurons in the modulation of specific hippocampal circuits in memory processes. The second part of the Thesis focused on subcellular location of CB1 activation in D1 positive cells. Indeed, besides the canonical regulation of neuronal activity by plasma membrane CB1 receptor, recent evidence suggests the involvement of mitochondrial CB1 receptor (mtCB1) in the regulation of bioenergetic processes which impacts on synaptic transmission and amnesic effects of cannabinoids. We found that mtCB1 receptors in hippocampal D1-positive neurons is not required for physiological regulation of memory formation per se but its activation is required for THC- induced memory impairment. Looking for the intracellular and intra-mitochondrial G-protein signaling involved in these processes, we developed a new chemogenetic strategy which specifically modulates the mitochondrial G-protein signaling and we observed its contribution in brain mitochondrial activity and cognitive functions. Specific chemogenetic activation of mitochondrial G- protein signaling results in increased mitochondrial respiration which in turns rescues THC-induced amnesic effect. Overall, the results of this Thesis indicate the mechanisms linking the diversity of cellular and subcellular CB1 receptors in higher brain functions, including learning and memory and provide the basis for the development of more selective and precise therapeutic strategies for cognitive disorders.