I028 Reduced hippocampal CB1R expression in GABAergic neurons drives synaptic and cognitive dysfunction in Huntington’s disease mice CB1R dysfunction of hippocampal inhibitory synapses drives cognitive dysfunction in Huntington´s disease mice

<h3>Background</h3> Although the formal diagnosis of HD is mainly based on the presence of motor abnormalities, most HD patients develop a decline in cognitive abilities that often precedes motor symptoms. Cognitive decline (CD) molecular mechanisms are still undetermined, and the hippocampus remains an underexplored region. The scarcity of knowledge arises the need for innovative molecular targets and emerge in the absence of CD treatments. Several evidences emphasized hippocampal CB1R (hCB1R) importance in cognitive functions, mostly in GABAergic and glutamatergic neurons. Interestingly, CB1R alteration has been revealed in several neurodegenerative disorders. Consequently, this project proposes CB1R as altered factor leading to CD in HD. <h3>Aims</h3> In HD male and female mice, we aim to:1) characterize hCB1R expression and function, 2) manipulate hCB1R in GABAergic/glutamatergic populations,3) explore the benefits of CB1R agonist WIN 55,212-2(WIN) for CD. Methods. hCB1R was assessed from pre to post-symptomatic stages in GABAergic/glutatamergic cells. Cognitive performances were evaluated after viral increase of hCB1R in GABAergic/glutamatergic cells. WIN benefits were proved on behavior and synaptic plasticity measuring GABA/glutamatergic transmission and CB1R density. <h3>Results</h3> hCB1R decreases in HD mice, specifically in GABAergic neurons. GABAergic transmission is altered and viral hCB1R increase in GABAergic cells ameliorate CD in HD mice. WIN treatment rescues CD, ameliorates CB1R levels, dendritic spines and GABAergic transmission in HD mice hippocampus (Figure 1). <h3>Conclusions</h3> Results showed alteration in the inhibitory/excitatory balance of HD mice and confirm hCB1R as crucial target for CD in HD. CB1R functional activation in GABAergic cells rescues CD in mice and cannabinoid compound assumes benefic role on CD.