Depolarization-induced suppression of inhibition
Encyclopedia
Depolarization-induced suppression of inhibition (DSI) is the classical and original electrophysiological
example of endocannabinoid function in the central nervous system
. Prior to the demonstration that DSI was dependent on the cannabinoid CB1
receptor function, there was no way of producing an in vitro endocannabinoid mediated effect.
DSI is classically produced in a brain slice experiment (i.e. a 300-400 µm slice of brain, with intact axons and synapses) where a single neuron is "depolarized" (the normal −70 mV potential across the neuronal membrane is reduced, usually to −30 to 0 mV) for a period of 1 to 10 seconds. After the depolarization, inhibitory GABA
mediated neurotransmission is reduced. This has been demonstrated to be caused by the release of endogenous cannabinoids from the depolarized neuron which diffuses to nearby neurons, and binds and activates CB1
receptors, which act presynaptically to reduce neurotransmitter release.
then confirmed in the hippocampus
by Pitler & Alger, 1992.
These groups were studying the responses of large pyramidal projection neurons to GABA
, the main inhibitory neurotransmitter
in the central nervous system. GABA
is typically released by small interneurons in many regions of the brain, where its job is to inhibit the activity of primary neurons, such as the CA1 pyramidal neurons of the hippocampus or the Purkinje cells of the cerebellum. Activation of GABA receptors on these cells, whether they are ionotropic or metabotropic, typically results in the influx of chloride ions into that target cell. This build-up of negative charge from the chloride ions results in the hyperpolarization
of the target cell, making it less likely to fire an action potential
. Accordingly, any ionic current that hyperpolarizes a cell is called an inhibitory current.
In their experiments with projection neurons in the hippocampus and cerebellum, both groups noticed that a train of action potentials in these cells resulted in a temporary reduction in inhibitory currents caused by GABA-ergic interneurons. Since this reduction of inhibitory currents could be invoked simply by depolarization
of the target cell, this phenomenon was termed depolarization-induced suppression of inhibition, or DSI. While initially discovered in CA1 neurons of the hippocampus and Purkinje cells in the cerebellum, DSI is a pretty ubiquitous phenomenon and has been demonstrated in other areas of the brain such as the basal ganglia
, the cortex
, the amygdala
, and the hypothalamus
(Katona et al. 2001, Jo et al. 2005, Bodor et al. 2005, Matyas et al. 2006)
The chemical messengers presumed to be responsible for mediating DSI was discovered by three separate groups in 2001. Wilson & Nicoll (2001) published their work in the prestigious journal, Nature, while the other two groups, Kreitzer & Regehr (2001) and Ohno-Shosaku et al. (2001), published in the same issue of another reputable journal, Neuron. All three demonstrated heavy involvement of the CB1 cannabinoid receptor
in DSI, suggesting that the endocannabinoids were the brain's mediators of DSI. They showed that cannabinoid receptor
agonists, drugs that mimic the actions of endocannabinoids or THC, could evoke the same reduction in inhibitory currents caused by DSI. They also demonstrated that DSI could be prevented by cannabinoid receptor
antagonists
, drugs that block the actions of cannabinoid compounds.
Other lines of evidence support the role of the CB1 receptor in DSI. This receptor is distributed very widely throughout the brain, covering all areas where DSI has been observed (Herkenham et al. 1990). The CB1 receptor also appears to be expressed mainly on GABA-ergic pre-synaptic terminals, making it an excellent candidate for mediating DSI (Matyas et al. 2006, Katona et al. 1999). In 2005, other groups began to demonstrate the involvement of the CB1 receptor in DSI in other regions of the brain (Jo et al. 2005, Bodor et al. 2005). Lastly, DSI research was finally applied to mice that had the CB1 receptor genetically "knocked-out". So far, these knock-out mice are not known to exhibit DSI in any regions of the brain, suggesting that the CB1 receptor is the crucial mediator for DSI (Kreitzer & Regehr 2001a, Ohno-Shosaku et al. 2002).
The discovery that DSI is mediated by endocannabinoids finally explained why both the CB1 receptor and the endocannabinoids are both so widely distributed in the brain. DSI is a very common form of short-term plasticity and thus needs to be mediated by a commonly found neurotransmitter. The use of endocannabinoids such as anandamide
and 2-arachidonoyl glycerol in this method of signalling is quite logical, since both molecules can be synthesized relatively easily from lipids in the plasma membrane, a fundamental constituent of all cells. DSI is therefore the primary cortical process mediated by the endocannabinoids, and may contribute to many forms of cortical plasticity and synaptic strengthening, such as in long-term potentiation
(Carlson et al. 2002).
. Some groups show that both DSI and DSE are lacking in these mice, while others have shown that DSE, but not DSI, can still be evoked in the knock-outs (Ohno-Shosaku et al. 2002, Hajos et al. 2001). The endocannabinoids may still mediate DSE too, but by acting at an as-of-yet unknown cannabinoid receptor. Interestingly, some work has shown that anandamide
can bind to the vannilloid receptor VR1
, the receptor responsible for mediating the effects of capsaicin
. This receptor is present in the brain, and anandamide actions at this receptor may potentially contribute to DSE (Cristino et al. 2006, Hajos et al. 2002). However DSE is currently a largely unexplored phenomenon and more research is needed to draw any firm conclusions.
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
example of endocannabinoid function in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Prior to the demonstration that DSI was dependent on the cannabinoid CB1
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
receptor function, there was no way of producing an in vitro endocannabinoid mediated effect.
DSI is classically produced in a brain slice experiment (i.e. a 300-400 µm slice of brain, with intact axons and synapses) where a single neuron is "depolarized" (the normal −70 mV potential across the neuronal membrane is reduced, usually to −30 to 0 mV) for a period of 1 to 10 seconds. After the depolarization, inhibitory GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
mediated neurotransmission is reduced. This has been demonstrated to be caused by the release of endogenous cannabinoids from the depolarized neuron which diffuses to nearby neurons, and binds and activates CB1
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
receptors, which act presynaptically to reduce neurotransmitter release.
History
DSI was discovered in 1992 by Vincent et al., (1992) working in purkinje cells of the cerebellumCerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
then confirmed in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
by Pitler & Alger, 1992.
These groups were studying the responses of large pyramidal projection neurons to GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
, the main inhibitory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the central nervous system. GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
is typically released by small interneurons in many regions of the brain, where its job is to inhibit the activity of primary neurons, such as the CA1 pyramidal neurons of the hippocampus or the Purkinje cells of the cerebellum. Activation of GABA receptors on these cells, whether they are ionotropic or metabotropic, typically results in the influx of chloride ions into that target cell. This build-up of negative charge from the chloride ions results in the hyperpolarization
Hyperpolarization
Hyperpolarization has several meanings:* Hyperpolarization occurs when the strength of the electric field across the width of a cell membrane increases...
of the target cell, making it less likely to fire an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
. Accordingly, any ionic current that hyperpolarizes a cell is called an inhibitory current.
In their experiments with projection neurons in the hippocampus and cerebellum, both groups noticed that a train of action potentials in these cells resulted in a temporary reduction in inhibitory currents caused by GABA-ergic interneurons. Since this reduction of inhibitory currents could be invoked simply by depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
of the target cell, this phenomenon was termed depolarization-induced suppression of inhibition, or DSI. While initially discovered in CA1 neurons of the hippocampus and Purkinje cells in the cerebellum, DSI is a pretty ubiquitous phenomenon and has been demonstrated in other areas of the brain such as the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, and the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
(Katona et al. 2001, Jo et al. 2005, Bodor et al. 2005, Matyas et al. 2006)
DSI mediation by endocannabinoids
DSI was thought to be due to a reduction in pre-synaptic neurotransmitter release for 2 reasons. 1) The magnitudes of spontaneously evoked inhibitory post-synaptic currents (IPSCs), caused by the release of a single pre-synaptic vesicle filled with GABA, remained unchanged and 2) The cellular responses to exogenously applied GABA remained the same. These observations suggested that no changes occurred in the post-synaptic cell to change its responsiveness to GABA during DSI. Somehow, DSI appeared to be mediated by a retrograde synaptic messenger whose synthesis or release was stimulated by the depolarization of the target cell. This messenger then diffused "backwards" to the pre-synaptic cell, where it caused a reduction in neurotransmitter release.The chemical messengers presumed to be responsible for mediating DSI was discovered by three separate groups in 2001. Wilson & Nicoll (2001) published their work in the prestigious journal, Nature, while the other two groups, Kreitzer & Regehr (2001) and Ohno-Shosaku et al. (2001), published in the same issue of another reputable journal, Neuron. All three demonstrated heavy involvement of the CB1 cannabinoid receptor
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
in DSI, suggesting that the endocannabinoids were the brain's mediators of DSI. They showed that cannabinoid receptor
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
agonists, drugs that mimic the actions of endocannabinoids or THC, could evoke the same reduction in inhibitory currents caused by DSI. They also demonstrated that DSI could be prevented by cannabinoid receptor
Cannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, drugs that block the actions of cannabinoid compounds.
Other lines of evidence support the role of the CB1 receptor in DSI. This receptor is distributed very widely throughout the brain, covering all areas where DSI has been observed (Herkenham et al. 1990). The CB1 receptor also appears to be expressed mainly on GABA-ergic pre-synaptic terminals, making it an excellent candidate for mediating DSI (Matyas et al. 2006, Katona et al. 1999). In 2005, other groups began to demonstrate the involvement of the CB1 receptor in DSI in other regions of the brain (Jo et al. 2005, Bodor et al. 2005). Lastly, DSI research was finally applied to mice that had the CB1 receptor genetically "knocked-out". So far, these knock-out mice are not known to exhibit DSI in any regions of the brain, suggesting that the CB1 receptor is the crucial mediator for DSI (Kreitzer & Regehr 2001a, Ohno-Shosaku et al. 2002).
The discovery that DSI is mediated by endocannabinoids finally explained why both the CB1 receptor and the endocannabinoids are both so widely distributed in the brain. DSI is a very common form of short-term plasticity and thus needs to be mediated by a commonly found neurotransmitter. The use of endocannabinoids such as anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
and 2-arachidonoyl glycerol in this method of signalling is quite logical, since both molecules can be synthesized relatively easily from lipids in the plasma membrane, a fundamental constituent of all cells. DSI is therefore the primary cortical process mediated by the endocannabinoids, and may contribute to many forms of cortical plasticity and synaptic strengthening, such as in long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(Carlson et al. 2002).
A note on DSE
While working with the cerebellum, Kreitzer's group also discovered that depolarization of Purkinje cells could also cause a temporary reduction in excitatory input into these cells from both climbing fibres and parallel fibres (Kreitzer et al. 2001b). This phenomenon was termed depolarization-induced suppression of excitation (DSE), and differs from DSI only by the kind of neurotransmitter whose release is reduced. In the case of DSI, the result is a reduction in inhibitory GABA release, while in DSE the effect is a reduction in excitatory glutamate release. DSE was also found to occur in other regions of the brain, however the evidence for the involvement of the endocannabinoid receptor CB1 in this process is not as solid as it is for DSI. Both DSI and DSE have been studied in the CB1 knock-out miceKnockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
. Some groups show that both DSI and DSE are lacking in these mice, while others have shown that DSE, but not DSI, can still be evoked in the knock-outs (Ohno-Shosaku et al. 2002, Hajos et al. 2001). The endocannabinoids may still mediate DSE too, but by acting at an as-of-yet unknown cannabinoid receptor. Interestingly, some work has shown that anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
can bind to the vannilloid receptor VR1
TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
, the receptor responsible for mediating the effects of capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
. This receptor is present in the brain, and anandamide actions at this receptor may potentially contribute to DSE (Cristino et al. 2006, Hajos et al. 2002). However DSE is currently a largely unexplored phenomenon and more research is needed to draw any firm conclusions.
Further reading
- Alger BE. (2002). Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 68:247-286.
- Freund TF, Katona I, Piomelli D. (2003). Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017-1066.