Depolarization-induced suppression of inhibition is the classical and original

electrophysiological Electrophysiology (from Greek , ''ēlektron'', "amber" etymology of "electron"">Electron#Etymology">etymology of "electron" , ''physis'', "nature, origin"; and , ''-logia'') is the branch of physiology that studies the electrical properties of bi ...

example of

endocannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

function in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. Prior to the demonstration that depolarization-induced suppression of inhibition was dependent on the cannabinoid CB1 receptor function, there was no way of producing an ''in vitro''

mediated effect. Depolarization-induced suppression of inhibition 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.

History

Depolarization-induced suppression of inhibition was discovered in 1992 by Vincent et al., (1992) working in purkinje cells of the

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

then confirmed in the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

by Pitler & Alger, 1992. These groups were studying the responses of large pyramidal projection neurons to GABA, the main inhibitory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

in the central nervous system. GABA is typically released by small

interneurons Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. In ...

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 Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

metabotropic A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...

, 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 An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

. 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 An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, c ...

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 In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

of the target cell, this phenomenon was termed depolarization-induced suppression of inhibition. While initially discovered in CA1 neurons of the hippocampus and Purkinje cells in the cerebellum, depolarization-induced suppression of inhibition is a pretty ubiquitous phenomenon and has been demonstrated in other areas of the brain such as the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...

, the

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

, the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...

, and the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

(Katona ''et al.'' 2001, Jo ''et al.'' 2005, Bodor ''et al.'' 2005, Matyas ''et al.'' 2006)

Depolarization-induced suppression of inhibition mediation by endocannabinoids

Depolarization-induced suppression of inhibition 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 depolarization-induced suppression of inhibition. Somehow, depolarization-induced suppression of inhibition 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 depolarization-induced suppression of inhibition 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 receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recepto ...

in depolarization-induced suppression of inhibition, suggesting that the

endocannabinoids Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

were the brain's mediators of depolarization-induced suppression of inhibition. They showed that

agonists, drugs that mimic the actions of endocannabinoids or THC, could evoke the same reduction in inhibitory currents caused by depolarization-induced suppression of inhibition. They also demonstrated that depolarization-induced suppression of inhibition could be prevented by

antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

, drugs that block the actions of cannabinoid compounds. Other lines of evidence support the role of the CB1 receptor in depolarization-induced suppression of inhibition. This receptor is distributed very widely throughout the brain, covering all areas where depolarization-induced suppression of inhibition 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 depolarization-induced suppression of inhibition (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, depolarization-induced suppression of inhibition 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 depolarization-induced suppression of inhibition is mediated by endocannabinoids finally explained why both the CB1 receptor and the endocannabinoids are both so widely distributed in the brain. Depolarization-induced suppression of inhibition 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 (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...

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. Depolarization-induced suppression of inhibition 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 In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...

(Carlson ''et al.'' 2002).

A note on depolarization-induced suppression of excitation

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 Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

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 mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important ...

. 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 a yet unknown cannabinoid receptor. Some work has shown that

can bind to the vannilloid receptor VR1, the receptor responsible for mediating the effects of

capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...

. 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.

References

* {{Cite journal , vauthors = Bodor AL, Katona I, Nyiri G, Mackie K, Ledent C, Hajos N, Freund TF , date=July 2005 , title = Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types , journal = J Neurosci , volume = 25 , issue = 29 , pages = 6845–6856 , doi = 10.1523/JNEUROSCI.0442-05.2005 , pmid = 16033894 , pmc=6725346 , doi-access = free *Carlson G, Wang Y, Alger BE. (2002) Endocannabinoids facilitate the induction of LTP in the hippocampus. Nat Neurosci. Aug;5(8):723-4. *Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V. (2006) Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. Apr 5; In Press. *Hajos N, Freund TF. (2002) Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology. Sep;43(4):503-10. *Hajos N, Ledent C, Freund TF. (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 106(1):1-4. *Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. Mar;87(5):1932-6. *Jo YH, Chen YJ, Chua SC Jr, Talmage DA, Role LW. (2005) Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron. Dec 22;48(6):1055-66. *Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, Freund TF. (2001) Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci. Dec 1;21(23):9506-18. *Katona I, Sperlagh B, Sik A, Kofalvi A, Vizi ES, Mackie K, Freund TF. (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. Jun 1;19(11):4544-58. *Kreitzer AC, Regehr WG. (2001a). Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron. 29(3):717-27 *Kreitzer AC, Regehr WG. (2001b) Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J Neurosci. Oct 15;21(20):RC174. *Matyas F, Yanovsky Y, Mackie K, Kelsch W, Misgeld U, Freund TF. (2006) Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia. Neuroscience. 137(1):337-61. *Ohno-Shosaku T, Tsubokawa H, Mizushima I, Yoneda N, Zimmer A, Kano M. (2002) Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses. J Neurosci. May 15;22(10):3864-72. *Ohno-Shosaku T, Maejima T, Kano M. (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron. 29(3):729-38 *Pitler TA, Alger BE. (1992). Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J Neurosci. 12:4122-4132. *Vincent P, Armstrong CM, Marty A. (1992) Inhibitory synaptic currents in rat cerebellar Purkinje cells: modulation by postsynaptic depolarization. J. Physiol. 456, p. 453–471. *Wilson RI, Nicoll RA. (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature. 410(6828):588-92

History

Depolarization-induced suppression of inhibition mediation by endocannabinoids

A note on depolarization-induced suppression of excitation

References

Further reading