AbstractAlthough the cannabinoid receptor 2 (CB₂R) is often thought to play a role mainly outside the brain several publications unequivocally showed the presence of CB₂R on hippocampal principal neurons. Activation of CB₂R produced a long-lasting membrane potential hyperpolarization, altered the input/output function of CA2/3 principal neurons and produced alterations in gamma oscillations. However, other cellular, molecular and behavioral consequences of hippocampal CB₂R signaling have not been studied in detail. Here we demonstrate that the deletion of CB₂ leads to a highly significant increase in hippocampal synapsin-I expression levels and particle density, as well as increased vesicular GABA transporter (vGAT) levels. This phenotype was restricted to females and not observed in males. Furthermore, we demonstrate an impairment of social memory in CB₂ deficient mice. Our results thus demonstrate that the lack of CB₂R leads to changes in the hippocampal synaptic landscape and reveals an important sex-specific difference in endocannabinoid signaling. This study supports a significant role of the CB₂R in modulation of different types of memory despite its low expression levels in the brain and provides more insight into a sex-specific role of CB₂R in synaptic architecture.