Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons.

Genetic inactivation of the cannabinoid CB1 receptor gene in different cell types in the brain has previously revealed necessary functions for distinct synaptic plasticity processes and behaviors. Here, we sought to identify CB1 receptor expression sites that are minimally required to reconstruct normal phenotypes. In a CB1-null background, we re-expressed endogenous CB1 receptors in forebrain GABAergic neurons, thereby assessing the sufficiency of CB1 receptors. Depolarization-induced suppression of inhibitory, but not excitatory, transmission was restored in hippocampal and amygdalar circuits. GABAergic CB1 receptors did not convey protection against chemically induced seizures, but prevented the spontaneous mortality observed in CB1 null mutants. Rescue of GABAergic CB1 receptors largely restored normal anxiety-like behavior but improved extinction of learned fear only marginally. This study illustrates that the approach of genetic reconstruction of complex behaviors is feasible. It also revealed distinct degrees of modulation for different emotional behaviors by the GABAergic population of CB1 receptors.