Publicação
Cannabinoid CB1 receptors modulation of hippocampal synaptic plasticity and the cross talk with adenosine A1 receptors
| Resumo: | Caffeine, an adenosine receptors antagonist, and marijuana, a cannabinoid receptor agonist, both affect human cognition. Their effects mostly result from their interference with the endogenous purinergic system and endocannabinoids (eCBs) system in the brain. Neuromodulators such as adenosine and endocannabinoids are important regulators of central nervous system neuronal activity. They are also able to modulate synaptic transmission individually. In the hippocampus, adenosine receptor type 1 (A₁R) and cannabinoid receptor type 1 (CB₁R) are the main receptors for adenosine and endocannabinoids, respectively. Both receptors are G-protein-coupled receptors that activate Gi/o. They are expressed in both inhibitory and excitatory neurons, and also in glial cells such as astrocytes. Chronic caffeine administration exacerbates spatial memory impairment caused by acute tetrahydrocannabinol (THC), which is the main psychoactive molecule of cannabis. In the hippocampus, A₁R and CB₁R are involved in memory impairment caused by CB₁R activation. It has also been shown that CB₁R activation decreases GABA and glutamate release in the hippocampus. These effects are partially reduced by co-activation of A₁R, suggesting an interaction between these modulatory pathways at the level of G-protein activation. The main sources of extracellular adenosine are 1) the extracellular production from the hydrolysis of adenine nucleotides and 2) transport from intracellular adenosine sources. eCB synthesis mostly results from the cleavage of postsynaptic membrane lipids. The activation of postsynaptic G-coupled glutamate metabotropic receptors induces the cleavage of postsynaptic membrane lipids, which is predominantly activated due to high neuronal firing. Thus, eCBs travel in a retrograde manner to activate astrocytic and nerve-terminal CB₁R, which inhibit neurotransmitter release and lead to several forms of short-term synaptic plasticity. CB₁Rs are endogenously activated by eCBs, mainly the fatty acids 2-arachidonoyl-sn-glycerol (2- AG) and anandamide. CB₁R agonists impair cognition and prevent long-term potentiation (LTP), synaptic plasticity induced by brief high-frequency neuronal firing, and synaptic transmission. Still, the influence of endogenously formed cannabinoids on hippocampal LTP remains ambiguous. In this study, it was possible to evaluate the influence of endocannabinoids on synaptic plasticity. I also wanted to determine if adenosine, through A₁R, could affect eCB signalling. The deletion or blockade of A₁R did not significantly change the modulatory effect of eCBs on LTP. I did not find evidence of a cross-talk mechanism at the synaptic plasticity level involving the two neuromodulators (A₁R and CB₁R). LTP induced by a weak θ-burst stimulation (wTBS) protocol was facilitated when blocking the action of eCB on CB₁R. In contrast, LTP induced by a strong θ-burst stimulation (sTBS) protocol was inhibited when the endogenous activation of CB₁R was blocked. This suggests that eCB inhibit weak LTP and facilitate strong LTP. The dual effect is mediated by 2-AG, suggesting that it acts as a high-pass filter that likely reduces the signal-to-noise-ratio of synaptic strengthening. The facilitatory effect of eCBs upon strong LTP depends on the activity of GABAergic interneurons. It was also described a modulatory role for A₁R on the CB₁R activation effect on inhibitory postsynaptic potential currents (IPSCs). When A₁R was blocked, the inhibitory effect of CB₁R activation on pyramidal cells was abolished, suggesting that an interaction between A₁R and CB₁R is at play. Overall, this work provides a better understanding of the neuromodulation of synaptic transmission and plasticity in the hippocampal CA1 region. It was able to show that CB₁R plays an important homeostatic role in synaptic plasticity phenomena through an A₁R independent process. However, A₁R seems to play a modulatory role in the action of eCB on inhibitory synaptic transmission. |
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| Autores principais: | Cruz, Armando Dulcídio da Silva |
| Assunto: | Canabinoides Receptores canabinoides CB 1 Hipocampo Plasticidade neuronal Receptor A1 de adenosina Neurociências Teses de doutoramento - 2020 |
| Ano: | 2020 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Caffeine, an adenosine receptors antagonist, and marijuana, a cannabinoid receptor agonist, both affect human cognition. Their effects mostly result from their interference with the endogenous purinergic system and endocannabinoids (eCBs) system in the brain. Neuromodulators such as adenosine and endocannabinoids are important regulators of central nervous system neuronal activity. They are also able to modulate synaptic transmission individually. In the hippocampus, adenosine receptor type 1 (A₁R) and cannabinoid receptor type 1 (CB₁R) are the main receptors for adenosine and endocannabinoids, respectively. Both receptors are G-protein-coupled receptors that activate Gi/o. They are expressed in both inhibitory and excitatory neurons, and also in glial cells such as astrocytes. Chronic caffeine administration exacerbates spatial memory impairment caused by acute tetrahydrocannabinol (THC), which is the main psychoactive molecule of cannabis. In the hippocampus, A₁R and CB₁R are involved in memory impairment caused by CB₁R activation. It has also been shown that CB₁R activation decreases GABA and glutamate release in the hippocampus. These effects are partially reduced by co-activation of A₁R, suggesting an interaction between these modulatory pathways at the level of G-protein activation. The main sources of extracellular adenosine are 1) the extracellular production from the hydrolysis of adenine nucleotides and 2) transport from intracellular adenosine sources. eCB synthesis mostly results from the cleavage of postsynaptic membrane lipids. The activation of postsynaptic G-coupled glutamate metabotropic receptors induces the cleavage of postsynaptic membrane lipids, which is predominantly activated due to high neuronal firing. Thus, eCBs travel in a retrograde manner to activate astrocytic and nerve-terminal CB₁R, which inhibit neurotransmitter release and lead to several forms of short-term synaptic plasticity. CB₁Rs are endogenously activated by eCBs, mainly the fatty acids 2-arachidonoyl-sn-glycerol (2- AG) and anandamide. CB₁R agonists impair cognition and prevent long-term potentiation (LTP), synaptic plasticity induced by brief high-frequency neuronal firing, and synaptic transmission. Still, the influence of endogenously formed cannabinoids on hippocampal LTP remains ambiguous. In this study, it was possible to evaluate the influence of endocannabinoids on synaptic plasticity. I also wanted to determine if adenosine, through A₁R, could affect eCB signalling. The deletion or blockade of A₁R did not significantly change the modulatory effect of eCBs on LTP. I did not find evidence of a cross-talk mechanism at the synaptic plasticity level involving the two neuromodulators (A₁R and CB₁R). LTP induced by a weak θ-burst stimulation (wTBS) protocol was facilitated when blocking the action of eCB on CB₁R. In contrast, LTP induced by a strong θ-burst stimulation (sTBS) protocol was inhibited when the endogenous activation of CB₁R was blocked. This suggests that eCB inhibit weak LTP and facilitate strong LTP. The dual effect is mediated by 2-AG, suggesting that it acts as a high-pass filter that likely reduces the signal-to-noise-ratio of synaptic strengthening. The facilitatory effect of eCBs upon strong LTP depends on the activity of GABAergic interneurons. It was also described a modulatory role for A₁R on the CB₁R activation effect on inhibitory postsynaptic potential currents (IPSCs). When A₁R was blocked, the inhibitory effect of CB₁R activation on pyramidal cells was abolished, suggesting that an interaction between A₁R and CB₁R is at play. Overall, this work provides a better understanding of the neuromodulation of synaptic transmission and plasticity in the hippocampal CA1 region. It was able to show that CB₁R plays an important homeostatic role in synaptic plasticity phenomena through an A₁R independent process. However, A₁R seems to play a modulatory role in the action of eCB on inhibitory synaptic transmission. |
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