Billet publié sur Bluesky le 12/01/2025 11:21

Résumé

Project Summary Phytocannabinoids represent a novel treatment strategy for numerous neurological conditions including autism spectrum disorder (ASD). However, despite promising results, current pre-clinical and clinical approaches are limited by the inclusion of the Δ9-THC which raises legal and safety concerns, especially when being used by children and adolescents. Therefore, we seek to optimize non-Δ9-THC containing cannabis-based treatment approaches by harnessing the phytochemical synergism that exists between the non-intoxicating phytocannabinoid, cannabidiol (CBD) and cannabis-derived terpenes. Reduced GABAergic signaling is a common underlying neurochemical signature of ASD, and we hypothesize that compositions that maximally restore the brain’s excitatory:inhibitory balance through boosting GABA signaling will reduce ASD phenotypes and provide developmental protection against abnormal brain development. To test this hypothesis, we propose to empirically assess the therapeutic efficacy of CBD alone and in combination with common cannabis terpenes on ASD-like phenotypes in the BTBR mouse model of ASD using electrophysiological (Aim 1), behavioral (Aim 2), and molecular techniques (Aim 3). In Aim 1, we will use local field potential and whole-cell patch-clamp slice-electrophysiology approaches as a screening platform for identifying CBD+terpene compositions that restore the excitatory:inhibitory balance and boost GABAA receptor mediated inhibition. In Aim 2, we will test the therapeutic efficacy of these CBD+terpene compositions on social and motor symptoms acutely in adulthood and separately following repeated exposure during a sensitive developmental window. In Aim 3, we will assess molecular markers of efficacy and safety from a subset of subjects undergoing developmental exposure to CBD and terpene compositions in Aim 2. We will measure critical drivers of synapse stabilization and plasticity using Westen Blot protein analysis to identify developmental shifts in brain derived neurotrophic factor and two-dimensional MALDI-TOF mass spectrometry to measure shifts in endocannabinoid expression (i.e., 2-AG and anandamide).Together, these experiments will provide the most comprehensive assessment of the proposed synergistic interactions between CBD and terpenes in a disease model to-date, reveal optimized non-Δ9-THC cannabis-based treatment approaches for ASD, and provide impactful undergraduate research experiences across numerous technical approaches in neuroscience.