Endocannabinoids and cortical plasticity: CB1R as a possible regulator of the excitation/inhibition balance in health and disease

Abstract

The endocannabinoid system has been linked to neurological disorders in which the excitation inhibition (E/I) balance of the neocortex is dysregulated, such as schizophrenia. The main endocannabinoid receptor type 1 of the central nervous system -CB1R -is expressed on different cell types, that when activated, modulate the cortical E/I balance. Here we review how CB1R signalling contributes to phases of heightened plasticity of the neocortex. We review the major role of the CB1R in cortical plasticity throughout life, including the early life sensory critical periods, the later maturation phase of the association cortex in adolescence, and the adult phase of sensory deprivationinduced cortical plasticity. Endocannabinoid-mediated long-term potentiation and depression of synapse strength fine-tune the E/I balance of visual, somatosensory and association areas. We emphasize how a distinct set of key endocannabinoid-regulated elements such as GABA and glutamate release, basket parvalbumin interneurons, somatostatin interneurons and astrocytes, are essential for normal cortical plasticity and dysregulated in schizophrenia. Even though a lot of data has been gathered, mechanistic knowledge about the exact CB1R-based modulation of excitation and/or inhibition is still lacking depending on cortical area and maturation phase in life. We emphasize the importance of creating such detailed knowledge for a better comprehension of what underlies the dysregulation of the neocortex in schizophrenic patients in adulthood. We propose that taking age, brain area and cell type into consideration when modulating the cortical E/I imbalance via cannabinoid-based pharmacology may pave the way for better patient care.

A Time-Course Study of the Expression Level of Synaptic Plasticity-Associated Genes in Un-Lesioned Spinal Cord and Brain Areas in a Rat Model of Spinal Cord Injury: A Bioinformatic Approach

“…The elective activation of glutamate neurons in the primary CTX-M was related to the functional prognosis of patients and can promote functional recovery after SCI [44]. Other regulated genes not directly related to the NMDA net includes Cnr1 (Cannabinoid Receptor 1), which is involved in sensory deprivation-induced cortical plasticity by mediating long-term potentiation and depression of synapse strength and the fine-tune of excitatory/inhibitory balance [45]. Several growth factor-and growth factor receptor encoding genes are down-regulated, e.g., Igf1, Ntf3, Ntrk2.…”

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

“…To test this hypothesis, we next investigated the possibility of reducing the spontaneous neuronal activity to rescue behaviorally-induced plasticity. The endocannabinoid system is a major neuromodulatory system with anti-inflammatory properties and neuroprotective effects both in vitro and in vivo 34,35 and is widely described in the somatosensory cortex [36][37][38][39] . Furthermore, endocannabinoids are released on-demand in an activity-dependent fashion 25 and can set the level of activity of neuronal networks 21 .…”

The endogenous cannabinoid system modulates male sexual behavior expression

“…At the central nervous system (CNS) CB1R are especially abundant in the cortex, basal ganglia, hippocampus, and cerebellum ( Mackie, 2005 ). The great majority of CB1R can be found on axon terminals and pre-terminal axon segments, while sparing the active zone ( Nyiri et al, 2005 ) and play a well-established role in CNS function and dysfunction ( Durieux et al, 2022 ). By contrast, CB2R were found to play a central role in the immune system ( Leleu-Chavain et al, 2013 ), while in the CNS, CB2R are predominantly expressed in microglia and only a few years ago were they identified on neurons, at the postsynaptic somatodendritic region, in discrete areas of the brain ( Van Sickle et al, 2005 ; Onaivi et al, 2008 ).…”