Cannabinoid control of hippocampal functions: the <i>where</i> matters

Robledo-Menendez, Almudena; Vella, Mark; Grandes, Pedro; Soria-Gómez, Edgar

doi:10.1111/febs.15907

Cited by 24 publications

(10 citation statements)

References 115 publications

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“…Furthermore, CB1 can also act pre-synaptically leading to the activation of the mitogen-activated protein kinase (MAPK) pathway ( Bouaboula et al, 1995 ), suggesting its involvement in cell proliferation and death processes in the hippocampus ( Derkinderen et al, 2001 ). Lastly, CB1 has also been found in alternative subcellular localizations with different functionalities from their plasma membrane equivalents, constituting a subpopulation with distinct pharmacological properties ( Robledo-Menendez et al, 2021 ).…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression

et al. 2021

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Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.

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Section: The Endocannabinoid Systemmentioning

confidence: 99%

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression

et al. 2021

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“…It is well known that endocannabinoids act as retrograde messengers; they are synthesized in a postsynaptic, activity-dependent manner, and stimulate Gi/o proteins coupled to presynaptic CB1 receptors (Kano et al, 2009;Brunt and Bossong, 2022;Dudok and Soltesz, 2022;Robledo-Menendez et al, 2022). Therefore, target sites of AM251 might be the presynaptic sites of synaptic couplings from neurons that produce seizure-like activity to phrenic motor neurons that could produce endocannabinoids in an activity-dependent manner (Fig.…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Cannabinoid receptors involved in descending inhibition on spinal seizure-like activity in the phrenic output

et al. 2023

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Seizure-like burst activities are induced by blockade of GABA A and/or glycine receptors in various spinal ventral roots of brainstem-spinal cord preparation from neonatal rodents. We found that this is not applicable to the phrenic nerve and that a new inhibitory descending pathway may suppress seizure-like activity in the phrenic nerve. Experiments were performed in brainstem-spinal cord preparation from newborn rats (age: 0-1 day). Left phrenic nerve and right C4 activities were recorded simultaneously. When GABA A and glycine receptors were blocked by 10 μM bicuculline and 10 μM strychnine (Bic+Str), seizure-like burst activities appeared in the fourth cervical ventral root (C4) but not the phrenic nerve. After making a transverse section at C1, the inspiratory burst activity disappeared from both C4 and the phrenic nerve, whereas seizure-like activity appeared in both nerves. We hypothesized that inhibitory descending pathways other than those via GABA A and/or glycine receptors (from the medulla to the spinal cord) work to avoid disturbance of regular respiratory-related diaphragm contraction by seizure-like activity. We found that cannabinoid receptor antagonist, AM251 was effective for the induction of seizure-like activity by Bic+Str in the phrenic nerve in brainstem-spinal cord preparation. Cannabinoid receptors may be involved in this descending inhibitory system.

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“…Physiological engagement of CB1 receptors by their endogenous ligands, the endocannabinoids, modulates many behavioral processes, including food intake, emotional responses and cognition 4 . Importantly, CB1 receptors can also be targeted by exogenous cannabinoids, such as Δ 9 -tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa . This exogenous, non-physiological activation might bear therapeutic properties, but it can also alter brain activity, impairing, for instance, cognitive, locomotor and perceptive functions 5 .…”

Section: Mainmentioning

confidence: 99%

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

Fernández‐Moncada

Fundazuri

Lavanco

et al. 2023

Preprint

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Control of brain energy metabolism and regulation of synaptic activity through gliotransmission are two important ways, through which astrocytes contribute to mental functions. However, the potential functional and molecular links between these two astrocyte-dependent processes have been scantly explored so far. Here we show that a lactate-dependent shift of glycolysis underlies the production of the gliotransmitter D-serine by acute activation of astrocyte type-1 cannabinoid (CB1) receptors, thereby gating synaptic and cognitive processes. Acute cannabinoid application causes a CB1 receptor-dependent rapid and reversible increase of lactate production and release in primary astrocyte cultures. As shown before, mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) were impaired in a novel object recognition (NOR) task. Notably, this phenotype was rescued not only by the gliotransmitter D-serine, but also by its precursor L-serine. Surprisingly, the administration of lactate also reverted the memory impairment of GFAP-CB1-KO mice. This rescue effect was abolished by in vivo blockade of the astrocyte-specific phosphorylated pathway (PP), which diverts glycolysis towards L-serine synthesis, suggesting that lactate itself might promote the accumulation of this amino acid. Consistent with this idea, lactate increased the co-agonist occupancy of CA1 post-synaptic hippocampal NMDA receptors in a PP-dependent manner. By establishing a mechanistic link between lactate, serine availability, synaptic activity and behavior, these results reveal an unforeseen functional connection between energy metabolism and gliotransmission to control cognitive processes.

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Cannabinoid control of hippocampal functions: the where matters

Cited by 24 publications

References 115 publications

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression

Cannabinoid receptors involved in descending inhibition on spinal seizure-like activity in the phrenic output

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

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