26.3 Cell-Type–Specific Type 1 Cannabinoid Receptor Distribution Across the Human and Nonhuman Primate Cortex

Abstract

Alterations in the type-1 cannabinoid (CB1) receptor are implicated in various mental health disorders. CB1 participates in both depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE), suggesting CB1's involvement in both inhibitory and excitatory circuits. However, previous studies describing the distribution of CB1 in human and nonhuman primate cortex utilized antibodies that preferentially target CB1 at inhibitory boutons. Given CB1’s role in both DSI and DSE, understanding cell type–specific CB1 distribution may increase our insight into its regulation of excitatory-inhibitory balance. Here, we investigate CB1 distribution in both inhibitory and excitatory boutons using quantitative fluorescent microscopy. Coronal sections containing dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) from adult male macaques and humans are labeled with antibodies for CB1 (validated to target both excitatory and inhibitory boutons), the vesicular glutamate transporter 1 (VGLUT1; labeling intracortical excitatory boutons), and the vesicular GABA transporter (VGAT; labeling intracortical inhibitory boutons). Samples are imaged to visualize protein expression patterns within cortical regions and layers (10 imaged sites per layer for each brain region of each subject). Fluorescent intensities of CB1 label within boutons of each type are compared using multifactorial ANOVA. CB1 co-expression with both VGLUT1 and VGAT are visualized in axons and boutons in all brain regions of both nonhuman primate and human samples. CB1 fluorescent intensity is lower in excitatory boutons compared to inhibitory boutons across all areas (p < 0.01) and exhibits distinct patterns within each brain region and cortical layer. Previous studies describing the distribution of CB1 in human and nonhuman primate cortex utilized antibodies preferentially targeting CB1 at inhibitory boutons. Using a CB1 antibody that targets both excitatory and inhibitory boutons, we demonstrate distinct cell type–specific regional and laminar distributions of CB1 in the human and nonhuman primate cortex. This may increase our understanding of how CB1 differentially regulates excitatory-inhibitory balance within these areas, and whether cell type–specific CB1 disturbances contribute to the development of psychopathology.