Hippocampal Cb₂ receptors: an untold story

The field of cannabinoid research has been receiving ever-growing interest. Ongoing debates worldwide about the legislation of medical cannabis further motivates research into cannabinoid function within the central nervous system (CNS). To date, two well-characterized cannabinoid receptors exist. While most research has investigated Cb₁ receptors (Cb₁Rs), Cb₂ receptors (Cb₂Rs) in the brain have started to attract considerable interest in recent years. With indisputable evidence showing the wide-distribution of Cb₂Rs in the brain of different species, they are no longer considered just peripheral receptors. However, in contrast to Cb₁Rs, the functionality of central Cb₂Rs remains largely unexplored. Here we review recent studies on hippocampal Cb₂Rs. While conflicting results about their function have been reported, we have made significant progress in understanding the involvement of Cb₂Rs in modulating cellular properties and network excitability. Moreover, Cb₂Rs have been shown to be expressed in different subregions of the hippocampus, challenging our prior understanding of the endocannabinoid system. Although more insight into their functional roles is necessary, we propose that targeting hippocampal Cb₂Rs may offer novel therapies for diseases related to memory and adult neurogenesis deficits.