Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus

Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB₁Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB₁Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB₂Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB₂R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB₂Rs and emphasizes their importance in basic neuronal transmission. The neuronal expression of CB₂Rs has been a matter of long-standing debate. Stempel et al. demonstrate that CB₂Rs are expressed in hippocampal principal cells and modulate neuronal function both in vitro and in vivo.