Depolarization-induced suppression of inhibition is the classical and original

electrophysiological Electrophysiology (from ee the Electron#Etymology, etymology of "electron" ; and ) is the branch of physiology that studies the electrical properties of biological cell (biology), cells and tissues. It involves measurements of voltage change ...

example of

endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

function in the

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

. 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 GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

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 (: cerebella or cerebellums; 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 it or eve ...

then confirmed in the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

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

, the main inhibitory

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

in the central nervous system.

is typically released by small

interneurons Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, ena ...

in many regions of the brain, where its job is to inhibit the activity of primary neurons, such as the CA1

pyramidal neurons Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cort ...

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: me ...

, 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 (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

. 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 (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific cell rapidly rises and falls. ...

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 (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

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 Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...

, 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 (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...

, and the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

(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 presynaptic neurotransmitter release for 2 reasons: # The magnitudes of spontaneously evoked inhibitory postsynaptic currents ( IPSCs), caused by the release of a single presynaptic vesicle filled with GABA, remained unchanged. # 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 of vertebrates a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cann ...

in depolarization-induced suppression of inhibition, suggesting that the

endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

were the brain's mediators of depolarization-induced suppression of inhibition. 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 depolarization-induced suppression of inhibition. They also demonstrated that depolarization-induced suppression of inhibition could be prevented by cannabinoid receptor

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

and

2-arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is pres ...

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 neuron ...

(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; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

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

knockout 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 importan ...

. 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 knockouts (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

anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

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

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

. 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