Form Of Long-term Synaptic Depression Research Articles

Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum

Drugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the µ-opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR-mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex–dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders.

Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in Hippocampus.

O-GlcNAcylation is a ubiquitous and dynamic post-translational modification involving the O-linkage of β-N-acetylglucosamine to serine/threonine residues of membrane, cytosolic, and nuclear proteins. This modification is similar to phosphorylation and regarded as a key regulator of cell survival and homeostasis. Previous studies have shown that phosphorylation of serine residues on synaptic proteins is a major regulator of synaptic strength and long-term plasticity, suggesting that O-GlcNAcylation of synaptic proteins is likely as important as phosphorylation; however, few studies have investigated its role in synaptic efficacy. We recently demonstrated that acutely increasing O-GlcNAcylation induces a novel form of LTD at CA3-CA1 synapses, O-GlcNAc LTD. Here, using hippocampal slices from young adult male rats and mice, we report that epileptiform activity at CA3-CA1 synapses, generated by GABAAR inhibition, is significantly attenuated when protein O-GlcNAcylation is pharmacologically increased. This dampening effect is lost in slices from GluA2 KO mice, indicating a requirement of GluA2-containing AMPARs, similar to expression of O-GlcNAc LTD. Furthermore, we find that increasing O-GlcNAcylation decreases spontaneous CA3 pyramidal cell activity under basal and hyperexcitable conditions. This dampening effect was also observed on cortical hyperexcitability during in vivo EEG recordings in awake mice where the effects of the proconvulsant pentylenetetrazole are attenuated by acutely increasing O-GlcNAcylation. Collectively, these data demonstrate that the post-translational modification, O-GlcNAcylation, is a novel mechanism by which neuronal and synaptic excitability can be regulated, and suggest the possibility that increasing O-GlcNAcylation could be a novel therapeutic target to treat seizure disorders and epilepsy.SIGNIFICANCE STATEMENT We recently reported that an acute pharmacological increase in protein O-GlcNAcylation induces a novel form of long-term synaptic depression at hippocampal CA3-CA1 synapses (O-GlcNAc LTD). This synaptic dampening effect on glutamatergic networks suggests that increasing O-GlcNAcylation will depress pathological hyperexcitability. Using in vitro and in vivo models of epileptiform activity, we show that acutely increasing O-GlcNAc levels can significantly attenuate ongoing epileptiform activity and prophylactically dampen subsequent seizure activity. Together, our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics.

Pull-Push Neuromodulation of LTP and LTD Enables Bidirectional Experience-Induced Synaptic Scaling in Visual Cortex

Neuromodulatory input, acting on G protein-coupled receptors, is essential for the induction of experience-dependent cortical plasticity. Here we report that G-coupled receptors in layer II/III of visual cortex control the polarity of synaptic plasticity through a pull-push regulation of LTP and LTD. In slices, receptors coupled to Gs promote LTP while suppressing LTD; conversely, receptors coupled to Gq11 promote LTD and suppress LTP. In vivo, the selective stimulation of Gs- or Gq11-coupled receptors brings the cortex into LTP-only or LTD-only states, which allows the potentiation or depression of targeted synapses with visual stimulation. The pull-push regulation of LTP/LTD occurs via direct control of the synaptic plasticity machinery and it is independent of changes in NMDAR activation or neuronal excitability. We propose these simple rules governing the pull-push control of LTP/LTD form a general metaplasticity mechanism that may contribute to neuromodulation of plasticity in other cortical circuits.

A late phase of LTD in cultured cerebellar Purkinje cells requires persistent dynamin-mediated endocytosis

Long-term synaptic depression (LTD) of cerebellar parallel fiber-Purkinje cell synapses is a form of use-dependent synaptic plasticity that may be studied in cell culture. One form of LTD is induced postsynaptically through an mGlu1/Ca influx/protein kinase Cα (PKCα) cascade, and its initial expression requires phosphorylation of ser-880 in the COOH-terminal PDZ-ligand region of GluA2 and consequent binding of PICK1. This triggers postsynaptic clathrin/dynamin-mediated endocytosis of GluA2-containing surface AMPA receptors. Cerebellar LTD also has a late phase beginning 45-60 min after induction that is blocked by transcription or translation inhibitors. Here, I have sought to determine the expression mechanism of this late phase of LTD by applying various drugs and peptides after the late phase has been established. Neither bath application of mGluR1 antagonists (JNJ-16259685, LY-456236) nor the PKC inhibitor GF-109203X starting 60-70 min after LTD induction attenuated the late phase. Similarly, achieving the whole cell configuration with a second pipette loaded with the peptide PKC inhibitor PKC(19-36) starting 60 min postinduction also failed to alter the late phase. Late internal perfusion with peptides designed to disrupt PICK1-GLUA2 interaction or PICK1 dimerization failed to impact late phase LTD expression. However, late internal perfusion with two different blockers of dynamin, the drug dynasore and a dynamin inhibitory peptide (QVPSRPNRAP), produced rapid and complete reversal of cerebellar LTD expression. These findings suggest that the protein synthesis-dependent late phase of LTD requires persistent dynamin-mediated endocytosis, but not persistent PICK1-GluA2 binding nor persistent activation of the upstream mGluR1/PKCα signaling cascade.

NMDA Receptors, mGluR5, and Endocannabinoids are Involved in a Cascade Leading to Hippocampal Long-Term Depression

In the CA1 region of the rat hippocampus, metabotropic glutamate receptor-5 (mGluR5) and cannabinoid-1 receptors (CB1Rs) are believed to participate in long-term synaptic depression (LTD). How mGluRs and CB1Rs interact to promote LTD remains uncertain. In this study, we examined LTD induced by CB1R agonists, mGluR5 agonists, and low-frequency electrical stimulation (LFS) of the Schaffer collateral pathway. Synthetic CB1R agonists induced robust LTD that was mimicked by the endocannabinoid (EC), noladin ether (NLDE), but not by anandamide. 2-Arachidonylglycerol (2AG) produced only a small degree of LTD. The selective mGluR5 agonist, namely (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), also induced robust LTD, and CHPG and NLDE occluded each other's effects. Similarly, CHPG and NLDE occluded LFS-induced LTD, and LTD resulting from all three treatments was blocked by a CB1R antagonist. CHPG-LTD and NLDE-LTD were insensitive to N-methyl-D-aspartate receptor (NMDAR) block, even though LFS-LTD requires NMDARs. LTD induced by LFS or CHPG, but not NLDE-LTD, was blocked by a selective mGluR5 antagonist. (RS)-3,5-dihydroxyphenylglycine (DHPG), a less selective group I mGluR agonist, also induced LTD, but its effects were not blocked by mGluR5 or CB1R antagonists. Furthermore, DHPG-LTD was additive with LFS-LTD and CHGP-LTD. These results suggest that NMDARs, mGluR5, and CB1Rs participate in a cascade that underlies LFS-LTD and that release of an EC and CB1R activation occur downstream of NMDARs and mGluR5. Furthermore, DHPG induces a form of LTD that differs mechanistically from LFS-induced depression.

Soluble Oligomers of Amyloid β Protein Facilitate Hippocampal Long-Term Depression by Disrupting Neuronal Glutamate Uptake

In Alzheimer's disease (AD), the impairment of declarative memory coincides with the accumulation of extracellular amyloid-beta protein (Abeta) and intraneuronal tau aggregates. Dementia severity correlates with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Abeta oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Abeta oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically evoked LTD in the CA1 region. Abeta-enhanced LTD was mediated by mGluR or NMDAR activity. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Abeta-facilitated LTD was mimicked by the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Abeta. We conclude that soluble Abeta oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.

Homer Interactions Are Necessary for Metabotropic Glutamate Receptor-Induced Long-Term Depression and Translational Activation

Group I metabotropic glutamate receptors (mGluRs) induce a form of long-term synaptic depression (mGluR-LTD) in area CA1 of the hippocampus that requires rapid protein synthesis. Although much is known about the mechanisms underlying mGluR-LTD, it is unclear how mGluRs couple to the effectors necessary for translation initiation. A clue comes from work in the mouse model of Fragile X syndrome [Fmr1 knock-out (KO) mice], where group 1 mGluR stimulation of protein synthesis is absent and mGluRs are less associated with the postsynaptic scaffolding protein Homer (Giuffrida et al., 2005). Here, we examined the role of Homer interactions in mGluR-LTD and mGluR signaling to protein synthesis machinery in wild-type and Fmr1 KO animals. A peptide that mimics the C-terminal tail of mGluR5 (mGluR5ct), shown previously to disrupt Homer interactions with mGluRs, blocks mGluR-LTD and mGluR-signaling to protein synthesis initiation in wild-type animals. Disruption of mGluR-Homer interactions selectively blocks mGluR activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), but not ERK (extracellular signal-regulated kinase), pathway and translation of a 5' terminal oligopyrimidine tract containing mRNA, Elongation factor 1alpha. In Fmr1 KO mice, mGluR-LTD is insensitive to disruption of Homer interactions and mGluR activation of PI3K-mTOR is lost. Our results find specific roles for Homer in mGluR signaling and plasticity and suggest that reduced mGluR-Homer interactions in Fmr1 KO mice lead to a deficit in mGluR stimulation of translation initiation.

Novel Form of Long-Term Synaptic Depression in Rat Hippocampus Induced By Activation of α1 Adrenergic Receptors

Neurons located in the locus coeruleus project to hippocampus and provide noradrenergic innervation necessary for hippocampal-dependent learning and memory. The mechanisms underlying the function of norepinephrine (NE) in memory processing are unknown but likely reside in the ability of NE to modulate the efficacy of glutamate synaptic transmission via activation of G-protein-coupled adrenergic receptors. Here we show that application of NE to rat hippocampal slices in vitro induces a long-term depression (LTD) of synaptic transmission at excitatory CA3-CA1 synapses that persists for >/=40 min after agonist washout. This LTD, which we refer to as NE LTD, is mediated by activation of alpha1 adrenergic receptors because the alpha1 agonist methoxamine can induce LTD at the same magnitude as that induced with the nonselective adrenergic agonist NE. Furthermore, NE LTD induced by either NE or methoxamine is blocked with the alpha1 receptor antagonist, prazosin, but is unaffected by antagonists of alpha2 and beta receptors. This plasticity persists in the presence of the GABA(A) receptor antagonist bicuculline, indicating that adrenergic modulation of GABA(A) receptor-mediated transmission does not underlie NE LTD. Induction of NE LTD requires presynaptic activity during agonist application and postsynaptic activation of N-methyl-d-aspartate receptors, fulfilling Hebbian criteria of coincident pre- and postsynaptic activity. The expression of NE LTD is likely to be postsynaptic because paired-pulse facilitation ratios during NE LTD expression are not different from baseline, similar to LTD induced by low-frequency stimulation. Thus we report the identification and characterization of a novel Hebbian form of LTD in hippocampus that is induced after activation of alpha1 adrenergic receptors. This plasticity may be a mechanism by which the adrenergic system participates in normal cognitive function.

Presynaptic long-term depression at a central glutamatergic synapse: a role for CaMKII.

CaMKII is a calcium-activated kinase that is abundant in neurons and has been strongly implicated in memory and learning. Here we show that low-frequency stimulation of glutamatergic afferents in hippocampal slices from juvenile domestic chicks results in long-term depression of synaptic transmission. This reduction does not require activation of NMDA or metabotropic glutamate receptors and does not require a rise in postsynaptic calcium. However, buffering presynaptic calcium prevents the reduction of the excitatory postsynaptic potential or current that is induced by low-frequency stimulation. In addition, application of the calmodulin antagonist calmidazolium, or the specific CaMKII antagonist KN-93, completely blocks long-term depression. These findings demonstrate a newly discovered form of long-term synaptic depression in the avian hippocampus.

Nitric-oxide-guanylyl-cyclase-dependent and -independent components of multiple forms of long-term synaptic depression.

Long-term depression (LTD) of synaptic strength is induced by glutamate-triggered increases in postsynaptic [Ca2+], through either influx or release from intracellular stores. Induction of LTD has also been reported to require release of Ca2+ from presynaptic stores and activation of presynaptic Ca2+/calmodulin-dependent protein kinase II. This finding leads to the hypothesis that the intercellular messenger nitric oxide (NO) may be a means by which postsynaptic Ca2+ triggers changes expressing LTD in presynaptic terminals. We report that bath application of the oxadiazoloquinoxalone derivative ODQ (4 microM), a selective inhibitor of NO-sensitive guanylyl cyclase (NOGC), markedly attenuated (90%) the magnitude of LTD induced by low-frequency stimulation (LFS; 1 Hz/15 min) of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Both the NO donor S-nitroso-N-acetylpenicillamine (100 microM) and the membrane-permeant cyclic guanine 3',5'-monophosphate (cGMP) analogue 8-(-4-chlorophenylthio) guanosine (8-pCPT)-cGMP (50 microM) enhanced the magnitude of LTD, which is consistent with he hypothesis that activation of NOGC plays a role in the induction of LTD. Nicotinamide (20 mM), an inhibitor of NO-activated ADP ribosyltransferase, did not impair the induction of LTD. In contrast to de novo LTD, the reversal of long-term potentiation by LFS (depotentiation) was only partially blocked (55%) by ODQ, and heterosynaptic LTD was not impaired at all, suggesting that there are both NOGC-dependent and -independent forms of LTD. Because postsynaptic intracellular infusion of ODQ (500 microM) failed to block the induction of LTD, we conclude that activation of presynaptic NOGC is a necessary step in the induction of an NOGC-dependent component of LTD.

Naloxone blocks long-term depression of excitatory transmission in rat CA1 hippocampus in vitro.

In rat hippocampal slices, high intensity tetanic stimulation (two 1 s trains of 100 Hz separated by 20 s, 3-5X intensity of the test stimulus) of the Schaffer collateral-commissural (SCC) fibers induced a long-term depression (LTD) of the negative field excitatory postsynaptic potentials (fEPSP) in stratum radiatum of the CA1 region. The initial slope of the fEPSP, evoked by a single test shock applied to the SCC fibers, was depressed for a period longer than 40 min following such high intensity tetanic stimulation to this fiber system. However, the same tetanic stimulation delivered at low (test) intensity induced long-term potentiation (LTP) of the fEPSPs. Thus, similar patterns of stimulation can induce either LTP or LTD, depending on whether low- or high-intensity tetanic stimuli are delivered. The LTD induced by high strength tetanic stimulation was clearly blocked by the opioid antagonist naloxone (1 microM); however, the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (AP5; 50 microM) had no effect on the LTD. Our data suggest that the strong stimulation used for LTD induction may have activated other afferent fiber systems and/or local interneurons in addition to SCC fibers, such as the enkephalin-containing terminals of the perforant path (PP) projecting to the stratum lacunosum moleculare or opioid peptide-containing interneurons. Thus, the resulting release of endogenous opioid peptides could play a role in the cellular mechanisms involved in some forms of long-term synaptic depression.

LTD: many means to how many ends?

Several forms of long-term synaptic depression (LTD) have been identified in the hippocampus. Although these LTDs differ in their methods of induction, it remains unclear whether they converge upon some final common mechanism(s) of expression. In the present paper we review critical aspects of heterosynaptic and homosynaptic LTD induction and consider those findings relevant to the expression of each. In addition, we suggest several experimental approaches which may be of benefit in addressing the commonality of LTD expression mechanisms.