RESEARCH HIGHLIGHTS Nature Reviews Neuroscience | AOP, published online 11 June 2014; doi:10.1038/nrn3772
ENDOCANNABINOIDS
A protective receptor pool Δ9-tetrahydrocannabinol (THC) and that this protective effect of THC was reduced in slices from CB1RGludeficient mice. Together, these findings pointed to a neuroprotective action of CB1R signalling at gluta matergic, rather than GABAergic, neuron terminals. To provide further evidence for this idea, the authors used a pharmacogenetic approach to specifically control the activity of corticostriatal glutamatergic neu rons that project to the dorsolateral striatum (which is involved in motor control) in mice. Inducing the activity of these neurons increased glutamate transmission, caused excitotoxic damage in the striatum and impaired rotarod performance. Importantly, these effects could be prevented by intraperitoneal administration of THC (as well as by administration of an NMDA receptor antagonist). Huntington’s disease is associ ated with excitotoxic damage to striatal neurons, and previous studies showed that an absence of CB1Rs in mice expressing mutant huntingtin results in earlier appearance of disease symptoms. Could this be due to a lack of CB1R‑mediated inhibition of glutamate transmission, leading to glutamate excitotoxicity? To answer this question, the authors assessed the effect of an NMDA receptor antagonist in the offspring of R6/2 mice — an established model of Huntington’s disease — crossed with mice lacking CB1Rs. Doublemutant offspring had reduced striatal volume, showed excitotoxic damage in the striatum and had impaired rotarod performance compared with R6/2 control litter mates. Intraperitoneal injections with an NMDA receptor antagonist
prevented these effects, whereas administration of a type A GABA receptor antagonist did not. In addition, the authors generated R6/2 mice in which the expression of CB1Rs in glutamatergic (cortico striatal) or GABAergic (striatal) neu rons could be temporally controlled by Cre recombinase-mediated exci sion. This revealed that an absence of CB1Rs from glutamatergic neurons, but not the absence of these receptors from GABAergic neurons, exacer bated the striatal and behavioural phenotype of the mice. This study shows that activation of CB1Rs expressed on the terminals of glutamatergic neurons can prevent excitotoxicity by restricting gluta mate release. This pool of receptors may therefore be a potential thera peutic target for neurodegenerative diseases associated with excitotoxicity, including Huntington’s disease. Leonie Welberg ORIGINAL RESEARCH PAPER Chiarlone, A. et al. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/ pnas.1400988111 (2014)
NATURE REVIEWS | NEUROSCIENCE
the absence of CB1Rs from glutamatergic neurons increased the sensitivity of postsynaptic neurons to excitotoxicity
Image Source / Alamy
Endocannabinoids have neuro protective effects in animal models of neurodegenerative disorders, but the underlying mechanism has remained unclear. Guzmán and colleagues now show that the presence of CB1 cannabinoid receptors (CB1Rs) at the terminals of glutamatergic cortico striatal neurons prevents excitotoxic ity in the striatum and thereby has neuroprotective effects in a mouse model of Huntington’s disease. CB1Rs are highly expressed in the terminals of both GABAergic neurons and — to a lesser extent — glutamatergic neurons in the striatum as well as in other brain areas. Endocannabinoid signalling through these receptors inhibits presynaptic activity and thereby prevents exces sive neurotransmitter release. The authors set out to investigate whether the neuroprotective effect of endo cannabinoids involves receptors on GABAergic or glutamatergic neurons. They used mice that lacked CB1Rs either in glutamatergic neurons (CB1RGlu-deficient mice) or in GABAergic neurons (CB1RGABAdeficient mice). A low-dose injection of the NMDA receptor agonist quinolinic acid into the striatum of CB1RGlu-deficient mice induced excitotoxic damage in medium spiny neurons and impaired rotarod perfor mance (a measure of motor coordina tion), whereas such injections had no effect in CB1RGABA-deficient mice or wild-type mice. This suggested that the absence of CB1Rs from glutamatergic neurons increased the sensitivity of postsynaptic neurons to excitotoxicity. An experiment in cor ticostriatal slices showed that the exci totoxic damage caused by incubation with a high dose of quinolinic acid in wild-type slices could be prevented by co-incubation with the CB1R agonist
VOLUME 15 | JULY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
ENDOCANNABINOIDS
A protective receptor pool Δ9-tetrahydrocannabinol (THC) and that this protective effect of THC was reduced in slices from CB1RGludeficient mice. Together, these findings pointed to a neuroprotective action of CB1R signalling at gluta matergic, rather than GABAergic, neuron terminals. To provide further evidence for this idea, the authors used a pharmacogenetic approach to specifically control the activity of corticostriatal glutamatergic neu rons that project to the dorsolateral striatum (which is involved in motor control) in mice. Inducing the activity of these neurons increased glutamate transmission, caused excitotoxic damage in the striatum and impaired rotarod performance. Importantly, these effects could be prevented by intraperitoneal administration of THC (as well as by administration of an NMDA receptor antagonist). Huntington’s disease is associ ated with excitotoxic damage to striatal neurons, and previous studies showed that an absence of CB1Rs in mice expressing mutant huntingtin results in earlier appearance of disease symptoms. Could this be due to a lack of CB1R‑mediated inhibition of glutamate transmission, leading to glutamate excitotoxicity? To answer this question, the authors assessed the effect of an NMDA receptor antagonist in the offspring of R6/2 mice — an established model of Huntington’s disease — crossed with mice lacking CB1Rs. Doublemutant offspring had reduced striatal volume, showed excitotoxic damage in the striatum and had impaired rotarod performance compared with R6/2 control litter mates. Intraperitoneal injections with an NMDA receptor antagonist
prevented these effects, whereas administration of a type A GABA receptor antagonist did not. In addition, the authors generated R6/2 mice in which the expression of CB1Rs in glutamatergic (cortico striatal) or GABAergic (striatal) neu rons could be temporally controlled by Cre recombinase-mediated exci sion. This revealed that an absence of CB1Rs from glutamatergic neurons, but not the absence of these receptors from GABAergic neurons, exacer bated the striatal and behavioural phenotype of the mice. This study shows that activation of CB1Rs expressed on the terminals of glutamatergic neurons can prevent excitotoxicity by restricting gluta mate release. This pool of receptors may therefore be a potential thera peutic target for neurodegenerative diseases associated with excitotoxicity, including Huntington’s disease. Leonie Welberg ORIGINAL RESEARCH PAPER Chiarlone, A. et al. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/ pnas.1400988111 (2014)
NATURE REVIEWS | NEUROSCIENCE
the absence of CB1Rs from glutamatergic neurons increased the sensitivity of postsynaptic neurons to excitotoxicity
Image Source / Alamy
Endocannabinoids have neuro protective effects in animal models of neurodegenerative disorders, but the underlying mechanism has remained unclear. Guzmán and colleagues now show that the presence of CB1 cannabinoid receptors (CB1Rs) at the terminals of glutamatergic cortico striatal neurons prevents excitotoxic ity in the striatum and thereby has neuroprotective effects in a mouse model of Huntington’s disease. CB1Rs are highly expressed in the terminals of both GABAergic neurons and — to a lesser extent — glutamatergic neurons in the striatum as well as in other brain areas. Endocannabinoid signalling through these receptors inhibits presynaptic activity and thereby prevents exces sive neurotransmitter release. The authors set out to investigate whether the neuroprotective effect of endo cannabinoids involves receptors on GABAergic or glutamatergic neurons. They used mice that lacked CB1Rs either in glutamatergic neurons (CB1RGlu-deficient mice) or in GABAergic neurons (CB1RGABAdeficient mice). A low-dose injection of the NMDA receptor agonist quinolinic acid into the striatum of CB1RGlu-deficient mice induced excitotoxic damage in medium spiny neurons and impaired rotarod perfor mance (a measure of motor coordina tion), whereas such injections had no effect in CB1RGABA-deficient mice or wild-type mice. This suggested that the absence of CB1Rs from glutamatergic neurons increased the sensitivity of postsynaptic neurons to excitotoxicity. An experiment in cor ticostriatal slices showed that the exci totoxic damage caused by incubation with a high dose of quinolinic acid in wild-type slices could be prevented by co-incubation with the CB1R agonist
VOLUME 15 | JULY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
