Activation of Postsynaptic GABAB Receptors Modulates the Bursting Pattern and Synaptic Activity of Olfactory Bulb Juxtaglomerular Neurons..
TRPV1 activation by endogenous anandamide triggers postsynaptic long- term depression in dentate gyrus(1) - luobulingka的日志Received 2. June 2. 01. 0; Accepted 2. September 2. 01. 0; Published online 1. November 2. 01. 0TRPV1 activation by endogenous anandamide triggers postsynaptic long- term depression in dentate gyrus. Andrés E Chávez, Chiayu Q Chiu & Pablo E Castillo. Dominick P. Purpura, Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, USA. The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli.
Repetitive activation of postsynaptic GABA(A)receptors by rapid, focal agonist application onto intact rat striatal neurones in vitro. 作者: Behrends Jan C, 1. A reduction in postsynaptic 5-HT 1A receptor function in limbic areas has consistently been observed following exposure to chronic stress. To investigate the hypothesis. 1. Psychopharmacology (Berl). 2014 May;231(10):2067-75. doi: 10.1007/s00213-013-3350-z. Epub 2013 Nov 21. Activation of postsynaptic 5-HT1A receptors improve stress.
Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input- specific manner. This suppression was a result of Ca. AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long- term depression (TRPV1- LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor–independent manner.
TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus(1),luobulingka的网易博客,Luobulingka-Neuroscience..
Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1- mediated regulation of synaptic strength at central synapses. INTRODUCTIONThe TRPV1 or vanilloid VR1 receptor is part of a large family of transient receptor potential (TRP) channels, which typically acts as a molecular detector of noxious signals in primary sensory neurons. This receptor is a homotetrameric, nonselective ligand- gated cation channel that is activated by a wide range of stimuli, including heat, changes in p. H, exogenous compounds such as the pungent ingredient in hot chili pepper and endogenous lipid ligands (termed endovanilloids) such as anandamide (AEA)3. Although first identified and cloned in peripheral afferent fibers.
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TRPV1 is also expressed in the brain. Although the role of TRPV1 in the peripheral nervous system as mediator of noxious stimuli is well established, the function of TRPV1 in the brain is less understood. The presence of TRPV1 in the brain is supported by diverse experimental approaches, including immunohistochemistry. PCR (RT- PCR)9, 1. These studies showed that TRPV1 can be found in prefrontal cortex, amygdala, hypothalamus, periaqueductal gray, locus coeruleus, cerebellum, hippocampus and dentate gyrus. Functional studies have demonstrated that exogenous activation of TRPV1 facilitates transmitter release not only in the spinal cord. Notably, TRPV1 receptors can also mediate a presynaptic form of long- term depression (LTD) at glutamatergic synapses onto CA1 inhibitory interneurons in the hippocampus.
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A similar form of TRPV1- dependent LTD has recently been reported in the developing superior colliculus. The precise mechanism by which putative presynaptic TRPV1 receptors can facilitate or suppress transmitter release is unclear. Anatomical evidence suggests that brain TRPV1 can also be found in the postsynaptic compartment. A recent study has shown that TRPV1 receptors mediate some AEA effects in the striatum.
Finally, TRPV1 knockout mice reportedly have deficits in hippocampus- dependent learning. TRPV1 receptors in rats suggest that hippocampal TRPV1 activation enables spatial memory retrieval under stressful conditions.
Although all these studies argue for the presence of TRPV1 receptors in the brain, a clear picture of how these receptors regulate neural function and, in particular, synaptic transmission has not yet emerged. To address this issue, we investigated the role of TRPV1 at excitatory synapses in the dentate gyrus, a brain structure in which these receptors are highly expressed. We found that exogenous activation of TRPV1 receptors reduced synaptic transmission in a transmitter release–independent manner.
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Moreover, TRPV1 activation by endogenous AEA triggered a form of postsynaptic LTD. These findings not only highlight the diverse mechanisms by which TRPV1 regulates synaptic function, but also demonstrate an unconventional method of endocannabinoid signaling in the brain. RESULTSTRPV1- mediated depression of excitatory transmission. To investigate the role of brain TRPV1, we recorded from dentate granular cells (DGCs) and elicited AMPA receptor–mediated excitatory postsynaptic currents (AMPAR- EPSCs) by stimulating medial perforant path (MPP) and mossy cell fibers (MCF) in acute hippocampal slices of rat (Supplementary Fig.
内容提示: Golgi Cell-Mediated Activation of Postsynaptic GABA BReceptors Induces Disinhibition of the Golgi Cell-GranuleCell Synapse in Rat.
Online Methods). Pharmacological activation of TRPV1 with the specific agonist capsaicin (CAP) selectively reduced MPP- EPSCs, but not MCF- EPSCs (Fig. Supplementary Fig. Supplementary Fig. Suppression of MPP- EPSC by 1 μM CAP was saturating (MPP, 7. P < 0. 0. 01, paired t test; Fig.
Supplementary Fig. M capsazepine (CPZ), a specific TRPV1 receptor antagonist (1. P = 0. 2. 15, paired t test; Fig.
Supplementary Fig. Supplementary Table 1). CPZ alone had no effect on basal synaptic transmission (Supplementary Fig. Postsynaptic loading of DGCs with another selective TRPV1 antagonist, AMG9.
AMG, 3 μM), also blocked CAP- mediated depression (1. P = 0. 1. 96, paired t test; Fig. CAP also mediated an input- specific depression of MPP transmission in mouse dentate gyrus (Supplementary Fig. Supplementary Table 1). In contrast with a recent report. CAP- mediated depression was absent in TRPV1 knockout mice (Trpv.
P < 0. 0. 01, paired t test; Trpv. P = 0. 5. 60, paired t test; Fig. TRPV1 activation depresses excitatory synaptic transmission in an input- specific manner. We next investigated the mechanism of this TRPV1- mediated depression. Figure 1: Functional evidence for TRPV1 receptors in the dentate gyrus. Pharmacological activation of TRPV1 receptors with the agonist capsaicin (CAP, 1 μM) depressed AMPAR- EPSC in an input- specific manner.
Top, representative traces of two consecutive AMPAR- EPSCs (1. M CAP at both medial perforant path (MPP) and mossy cell fibers (MCF). Bottom, summary plot showing the effect of CAP on AMPAR- EPSCs. Application of the group II m. Glu. R agonist DCG- IV (1 μM) selectively depressed MPP- EPSCs, but not MCF- EPSCs, and subsequent application of the AMPAR antagonist NBQX (1.
M) abolished the remaining DCG- IV–insensitive component. Average traces (top) and summary data (bottom) showing that pretreatment with the TRPV1 antagonist CPZ (1. M) or loading of DGCs with the antagonist AMG9. AMG, 3 μM) eliminated CAP- mediated depression of AMPAR- EPSC in the MPP. CAP- mediated depression of AMPAR- EPSC was also present in Trpv. Trpv. 1- /- , mice. The numbers of cells (c) or animals (a) are indicated in parentheses.
In all panels, averaged sample traces taken at times indicated by numbers are shown next to each summary plot. Summary data consist of mean ± s. If TRPV1 activation affected glutamate release. CAP would likely depress both AMPAR- and NMDA receptor (NMDAR)- mediated EPSCs to a similar extent. In contrast, we found that CAP had no effect on NMDAR- EPSCs monitored at different holding potentials (?
V, 1. 00. 9 ± 1. 3% of baseline, n = 5, P = 0. V, 1. 00. 2 ± 3. 4% of baseline, n = 5, P = 0. Fig. 2a and Supplementary Table 1), suggesting that TRPV1- mediated depression of MPP synaptic transmission is not a result of glutamate release modulation.
Two additional observations are consistent with this idea. First, CAP- mediated depression of MPP- DGC transmission was not associated with changes in paired pulse ratio (PPR) or coefficient of variation (1/CV2) in both rat and mouse (Supplementary Fig. Supplementary Table 2). Second, CAP reduced the amplitude, but not the frequency, of asynchronous MPP- EPSCs evoked in the presence of extracellular strontium (see Online Methods, Fig. Supplementary Fig. Supplementary Table 1), indicating that a reduction in the quantal size, rather than quantal content, likely underlies TRPV1- mediated depression of MPP synaptic transmission. Figure 2: Postsynaptic TRPV1- mediated suppression of excitatory transmission.
CAP exerted no effect on NMDAR- mediated transmission measured at - 4. V and +4. 0 m. V in the presence of 1. M NBQX. (b) Representative traces (left) and summary plot (right) showing that 1 μM CAP depressed the amplitude, but not the frequency, of asynchronous AMPA- EPSC. P < 0. 0. 1. (c) CAP selectively depressed AMPAR- mediated responses evoked by puffing 1 m. M glutamate in the MPP, but not the MCF, synaptic field in rat. Representative responses evoked in the MPP synaptic field before (black) and after CAP (gray) application are shown on the left. Vertical arrowheads indicate the time of glutamate puffs.
NBQX completely abolished glutamate puff–evoked EPSCs (light gray), indicating that the responses were mediated by AMPARs. The summarized time course of CAP- mediated effect is shown on the right. Representative traces (left) and summary plot (right) showing that CAP also mediated depression of AMPAR- mediated responses evoked by puffing glutamate in Trpv. Trpv. 1- /- , mice. The numbers of cells (c) or animals (a) are indicated in parentheses. Representative traces (left) and summary plot (right) showing that transient pharmacological activation of TRPV1 receptors triggered long- lasting depression of AMPAR- mediated transmission that cannot be rescued by subsequent application of the TRPV1 antagonist CPZ.
In all panels, averaged sample traces taken at times indicated by numbers are shown next to each summary plot. Summary data consist of mean ± s. To directly test whether a postsynaptic modification could account for the TRPV1- mediated depression of transmission, we examined the effects of CAP on DGC responses elicited by brief puffs of glutamate (Online Methods), a manipulation that shortcuts transmitter release.
The glutamate- evoked responses (monitored at - 6.