A combination of Δ9-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer’s disease

Background : Dysregulation of glutamatergic activity has been shown to contribute to cognitive impairment and to the progression of the neurodegenerative process in Alzheimer’s disease (AD). Previous data revealed that chronic treatment with a combination of two natural cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), reduces cognitive decline in APP/PS1 mice. Since the endogenous cannabinoid system plays a key role in the control of neuronal excitability, we hypothesize that the chronic treatment with the combination of THC and CBD might alleviate cognitive decline in APP/PS1 mice by modulating glutamate dynamics in the hippocampus. Methods : In vivo microdialysis was used to assess extracellular glutamate levels in the hippocampus of APP/PS1 and wild-type (WT) mice chronically treated with THC and CBD. The levels of glutamate transporters and of glutamate receptors and their associated signaling pathways were assessed by immunoblotting. Electrophysiological recordings were used to evaluate synaptic transmission and plasticity. Dendritic spine density and morphology was analyzed by DiI ballistic labeling. Results : Chronic treatment with the combination of THC and CBD reduced the extracellular glutamate levels in the hippocampus of APP/PS1 and WT mice in response to the depolarizing drug veratridine or the glutamate transporter GLT-1 inhibitor dihydrokainic acid. No relevant effects were observed in the levels of the main glutamate receptor subunits or transporters and in their associated signaling mediators after chronic treatment. Similarly, no significant treatment effects were observed in dendritic spine density and morphology in the hippocampus or in the induction of long-term potentiation in CA1 area in treated animals. However, the input-output curve revealed that chronic THC and CBD treatment reduced the basal excitability of hippocampal CA1 synapses in both APP/PS1 and WT mice. Conclusions : Our data suggest that the beneficial effects of these cannabinoids at the cognitive levels might be related to the modulation of glutamate dynamics in the hippocampus and support their potential therapeutic properties against AD.