Cannabis points to the synaptic pathology of mental disorders: how aberrant synaptic components disrupt the highest psychological functions

Abstract

Cannabis can elicit an acute psychotic reaction, and its long-term use is a risk factor for schizophrenia. The main active psychoactive ingredient ∆9-tetrahydrocannabinol (Δ9 -THC) activates cannabinoid 1 (CB1) receptors, which are localized to the terminals of glutamate and GABA neurons in the brain. The endogenous cannabinoids are involved in information processing and plasticity at synapses in the hippocampus, basal ganglia, and cerebral cortex. Exogenously applied CB1 receptor agonists disrupt neuronal dynamics and synaptic plasticity, resulting in cognitive deficits and impairment of the highest psychological functions. Various other pro-psychotic drugs, such as ketamine and methamphetamine, exert their effects in the same microdomain of synaptic spines as Δ9 -THC. Additionally, many of the most robust findings in psychiatric genetics include components that localize to dendritic spines and have important roles in information processing and plasticity.

Exploring causal mechanisms of psychosis risk

“…Specifically, gamma frequencies that modulate activity locally, are distantly modulated by theta oscillations, where gamma is nested into the phase of theta oscillations ( Canolty et al, 2006 ). GABAergic interneurons are understood to coordinate these oscillations ( Gonzalez-Burgos and Lewis, 2008 ) via endocannabinoid dependent mechanisms ( Morrison and Murray, 2020 ). Exogenously administered cannabinoids bind to CB1 receptors indiscriminately, and can therefore disrupt synchronisation ( Morrison and Murray, 2020 ; Skosnik et al, 2016 ) and cross-frequency phase coherence ( Kucewicz et al, 2011 ).…”

“…GABAergic interneurons are understood to coordinate these oscillations ( Gonzalez-Burgos and Lewis, 2008 ) via endocannabinoid dependent mechanisms ( Morrison and Murray, 2020 ). Exogenously administered cannabinoids bind to CB1 receptors indiscriminately, and can therefore disrupt synchronisation ( Morrison and Murray, 2020 ; Skosnik et al, 2016 ) and cross-frequency phase coherence ( Kucewicz et al, 2011 ). Furthermore, theta, alpha, and gamma power have been found to be decreased in heavy users compared to non-users in studies of evoked and resting state EEG, where the greater the cannabis use, the lower the EEG power ( Edwards et al, 2009 , Skosnik et al, 2006 ).…”

Perturbation of 3D nuclear architecture, epigenomic aging and dysregulation, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 2—Metabolome, immunome, synaptome

“…However, this number can be multiplied by the many astrocytes which are the most numerous cells in the brain and also participate actively in tripartite synaptic trafficking in many ways ( 295 , 296 ). Dendritic spines are believed to be a key site of much brain computation, learning, and memory, and are involved in essentially all brain functions and numerous neuropsychiatric disorders including depression, schizophrenia, and autism ( 293 , 297 , 298 ). Dendritic spines comprise 70% of the synapses in the cortex and occur with a frequency of 10 per micrometer ( 293 ).…”

“…Given that mitochondria play such a key role in synaptoenergetics, it is clear that the general disruption of mitochondrial metabolism will necessarily perturb both neuronal and synaptic activity and epigenomic regulation. Given that synaptic dysregulation is a key component of most neuropsychiatric disorders, these disruptions are likely to have far reaching and protean manifestations ( 293 , 297 , 298 ). In view of the fact that both the brain and mitochondria also control systemic aging and disease ( 364 , 365 ) these impacts are likely to ramify beyond even psychiatry to the general domain of whole-body health.…”