Cannabinoid CB1 Receptor in Dorsal Telencephalic Glutamatergic Neurons: Distinctive Sufficiency for Hippocampus-Dependent and Amygdala-Dependent Synaptic and Behavioral Functions

Abstract

A major goal in current neuroscience is to understand the causal links connecting protein functions, neural activity, and behavior. The cannabinoid CB1 receptor is expressed in different neuronal subpopulations, and is engaged in fine-tuning excitatory and inhibitory neurotransmission. Studies using conditional knock-out mice revealed necessary roles of CB1 receptor expressed in dorsal telencephalic glutamatergic neurons in synaptic plasticity and behavior, but whether this expression is also sufficient for brain functions is still to be determined. We applied a genetic strategy to reconstitute full wild-type CB1 receptor functions exclusively in dorsal telencephalic glutamatergic neurons and investigated endocannabinoid-dependent synaptic processes and behavior. Using this approach, we partly restored the phenotype of global CB1 receptor deletion in anxiety-like behaviors and fully restored hippocampus-dependent neuroprotection from chemically induced epileptiform seizures. These features coincided with a rescued hippocampal depolarization-induced suppression of excitation (DSE), a CB1 receptor-dependent form of synaptic plasticity at glutamatergic neurons. By comparison, the rescue of the CB1 receptor on dorsal telencephalic glutamatergic neurons prolonged the time course of DSE in the amygdala, and impaired fear extinction in auditory fear conditioning. These data reveal that CB1 receptor in dorsal telencephalic glutamatergic neurons plays a sufficient role to control neuronal functions that are in large part hippocampus-dependent, while it is insufficient for proper amygdala functions, suggesting an unexpectedly complex circuit regulation by endocannabinoid signaling in the amygdala. Our data pave the way to a better understanding of neuronal networks in the context of behavior, by fine-tuned interference with synaptic transmission processes.

Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB 1 receptors on developing cortical neurons

“…2F; THC vs. vehicle, 81.3 ± 4.1 and 96.0 ± 3.5 mg/kg, respectively; P < 0.01). This effect of prenatal cannabinoid administration was reminiscent of the adult CB 1 −/− mice phenotype, which displays increased seizure susceptibility in the kainic acid model (20,21). Importantly, we found no further enhancement of PTZ susceptibility in THC-treated CB 1 −/− mice with respect to their vehicletreated counterparts, thus confirming the CB 1 R specificity of THC action ( Fig.…”

“…CB 1 R expression rescue was performed in Stop-CB 1 mice by using Nex-Cre, Dlx5/6-Cre, and EIIa-Cre-driven recombination (20,21). Immunohistological characterization of different CB 1 R-rescue mice was performed in P2.5 and P20 brain samples.…”

“…To unequivocally determine the neuronal identity of embryonic THC-exposure actions, we made use of a Cre-mediated, lineage-specific, embryonic CB 1 R expression-rescue strategy in a CB 1 R-null background (Stop-CB 1 mice) (21). The selective expression of CB 1 R in dorsal telencephalic glutamatergic neurons (Glu-CB 1 -RS mice) was achieved by expressing Cre under the regulatory elements of the Nex gene (21). In addition, we rescued CB 1 R expression in forebrain GABAergic neurons (GABA-CB 1 -RS mice) by using the Dlx5/6-Cre mouse line (20).…”

“…*P < 0.05, **P < 0.01 vs. vehicle-treated CB 1 +/− mice. rescue approach driven by EIIa-Cre (CB 1 -RS) was also used (21). Characterization of CB 1 R expression by immunofluorescence was performed in the different mouse lines.…”

Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation

“…To evaluate whether the expression of CB1 receptor in DBH + cells is not only necessary but also sufficient (32) to produce stress-induced memory deficits, specific mouse lines were developed to rescue CB1 receptor expression globally (CB1-RS mice) (32) or specifically in DBH + cells (DBH-CB1-RS mice) ( Fig. S6 B and C).…”