AUTHOR=Humble James , Kozloski James R. TITLE=Cannabinoid signaling and risk in Huntington's disease JOURNAL=Frontiers in Computational Neuroscience VOLUME=16 YEAR=2022 URL=https://www.frontiersin.org/journals/computational-neuroscience/articles/10.3389/fncom.2022.903947 DOI=10.3389/fncom.2022.903947 ISSN=1662-5188 ABSTRACT=

Dysregulated endocannabinoid (eCB) signaling and the loss of cannabinoid receptors (CB1Rs) are important phenotypes of Huntington's disease (HD) but the precise contribution that eCB signaling has at the circuit level is unknown. Using a computational model of spiking neurons, synapses, and eCB signaling, we demonstrate that eCB signaling functions as a homeostatic control mechanism, minimizing excess glutamate. Furthermore, our model demonstrates that metabolic risk, quantified by excess glutamate, increases with cortico-striatal long-term depression (LTD) and/or increased cortico-striatal activity, and replicates a progressive loss of cannabinoid receptors on inhibitory terminals as a function of the excitatory/inhibitory ratio.