scholarly journals Actomyosin-mediated nanostructural remodeling of the presynaptic vesicle pool by cannabinoids induces long-term depression

2018 ◽  
Author(s):  
Maureen H. McFadden ◽  
Hao Xu ◽  
Yihui Cui ◽  
Rebecca A. Piskorowski ◽  
Christophe Leterrier ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Synaptic Function ◽  
Actin Binding ◽  
Functional Plasticity ◽  
Structural Reorganization ◽  
Long Term Depression ◽  
Dynamic Regulation ◽  
Presynaptic Vesicle

AbstractEndo- and exocannabinoids, such as the psychoactive component of marijuana, exert their effects on brain function by inducing several forms of synaptic plasticity through the modulation of presynaptic vesicle release1-3. However, the molecular mechanisms underlying the widely expressed endocannabinoid-mediated long-term depression3 (eCB-LTD), are poorly understood. Here, we reveal that eCB-LTD depends on the contractile properties of the pre-synaptic actomyosin cytoskeleton. Preventing this contractility, both directly by inhibiting non-muscle myosin II NMII ATPase and indirectly by inhibiting the upstream Rho-associated kinase ROCK, abolished long-term, but not short-term forms of cannabinoid-induced functional plasticity in both inhibitory hippocampal and excitatory cortico-striatal synapses. Furthermore, using 3D superresolution microscopy, we find an actomyosin contractility-dependent redistribution of synaptic vesicle pools within the presynaptic compartment following cannabinoid receptor activation, leading to vesicle clustering and depletion from the pre-synaptic active zone. These results suggest that cannabinoid-induced functional plasticity is mediated by a nanoscale structural reorganization of the presynaptic compartment produced by actomyosin contraction. By introducing the contractile NMII as an important actin binding/structuring protein in the dynamic regulation of synaptic function, our results open new perspectives in the understanding of mechanisms of synaptic and cognitive function, marijuana intoxication and psychiatric pathogenesis.

scholarly journals Dissecting the Roles of Kalirin-7/PSD-95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2020 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard Mains
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Synaptic Function ◽  
Nucleotide Exchange ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Knockout Animals

Abstract Background: Kalirin-7 (Kal7) is a multidomain scaffold and guanine nucleotide exchange factor localized to the postsynaptic density, where Kal7 is crucial for synaptic plasticity. Kal7 knockout mice exhibit marked suppression of long-term potentiation and long-term depression in hippocampus, cerebral cortex and spinal cord, with depressed surface expression of GluN2B receptor subunits and dramatically blunted perception of pain. Kal7 knockout animals show exaggerated locomotor responses to psychostimulants and self-administer cocaine more enthusiastically than wildtype mice. Results: To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we infused candidate intracellular interfering peptides to acutely challenge the synaptic function(s) of Kal7 with potential protein binding partners, to determine if plasticity deficits in Kal7-/- mice are the product of developmental processes since conception, or could be produced on a much shorter time scale. We demonstrated that these small intracellular peptides disrupted normal long-term potentiation and long-term depression, strongly suggesting that maintenance of established interactions of Kal7 with PSD-95 and/or GluN2B is crucial to synaptic plasticity. Conclusions: Blockade of the Kal7-GluN2B interaction was most effective at blocking long-term potentiation, but had no effect on long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

scholarly journals Muscarinic Receptor–Dependent Long-Term Depression in Rat Visual Cortex Is PKC Independent but Requires ERK1/2 Activation and Protein Synthesis

2007 ◽  
Vol 98 (4) ◽  
pp. 1862-1870 ◽  
Author(s):  
Portia A. McCoy ◽  
Lori L. McMahon
Keyword(s):  
Protein Synthesis ◽  
Visual Cortex ◽  
Muscarinic Receptor ◽  
Cholinergic System ◽  
Receptor Activation ◽  
Synaptic Function ◽  
Cholinergic Innervation ◽  
Long Term Depression ◽  
M1 Receptor

Intact cholinergic innervation of visual cortex is critical for normal processing of visual information and for spatial memory acquisition and retention. However, a complete description of the mechanisms by which the cholinergic system modifies synaptic function in visual cortex is lacking. Previously it was shown that activation of the m1 subtype of muscarinic receptor induces an activity-dependent and partially N-methyl-d-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at layer 4–layer 2/3 synapses in rat visual cortex slices in vitro. The cellular mechanisms downstream of the Gαq coupled m1 receptor required for induction of this LTD (which we term mLTD) are currently unknown. Here, we confirm a role for m1 receptors in mLTD induction and use a series of pharmacological tools to study the signaling molecules downstream of m1 receptor activation in mLTD induction. We found that mLTD is prevented by inhibitors of L-type Ca2+ channels, the Src kinase family, and the mitogen-activated kinase/extracellular kinase. mLTD is also partially dependent on phospholipase C but is unaffected by blocking protein kinase C. mLTD expression can be long-lasting (>2 h) and its long-term maintenance requires translation. Thus we report the signaling mechanisms underlying induction of an m1 receptor-dependent LTD in visual cortex and the requirement of protein synthesis for long-term expression. This plasticity could be a mechanism by which the cholinergic system modifies glutamatergic synapse function to permit normal visual system processing required for cognition.

scholarly journals Pilocarpine-Induced Status Epilepticus Is Associated with Changes in the Actin-Modulating Protein Synaptopodin and Alterations in Long-Term Potentiation in the Mouse Hippocampus

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Maximilian Lenz ◽  
Marina Ben Shimon ◽  
Thomas Deller ◽  
Andreas Vlachos ◽  
Nicola Maggio
Keyword(s):  
Synaptic Plasticity ◽  
Status Epilepticus ◽  
Molecular Mechanisms ◽  
Seizure Activity ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Stratum Radiatum ◽  
Actin Binding ◽  
Term Potentiation

Epilepsy is a complex neurological disorder which can severely affect neuronal function. Some patients may experience status epilepticus, a life-threatening state of ongoing seizure activity associated with postictal cognitive dysfunction. However, the molecular mechanisms by which status epilepticus influences brain function beyond seizure activity remain not well understood. Here, we addressed the question of whether pilocarpine-induced status epilepticus affects synaptopodin (SP), an actin-binding protein, which regulates the ability of neurons to express synaptic plasticity. This makes SP an interesting marker for epilepsy-associated alterations in synaptic function. Indeed, single dose intraperitoneal pilocarpine injection (250 mg/kg) in three-month-old male C57BL/6J mice leads to a rapid reduction in hippocampal SP-cluster sizes and numbers (in CA1 stratum radiatum of the dorsal hippocampus; 90 min after injection). In line with this observation (and previous work using SP-deficient mice), a defect in the ability to induce long-term potentiation (LTP) of Schaffer collateral-CA1 synapses is observed. Based on these findings we propose that status epilepticus could exert its aftereffects on cognition at least in part by perturbing SP-dependent mechanisms of synaptic plasticity.

scholarly journals Dissecting the Roles of Kalirin-7/PSD-95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2020 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard Mains
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Synaptic Function ◽  
Nucleotide Exchange ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Knockout Animals

Abstract Background: Kalirin-7 (Kal7) is a multidomain scaffold and guanine nucleotide exchange factor localized to the postsynaptic density, where Kal7 is crucial for synaptic plasticity. Kal7 knockout mice exhibit marked suppression of long-term potentiation and long-term depression in hippocampus, cerebral cortex and spinal cord, with depressed surface expression of GluN2B receptor subunits and dramatically blunted perception of pain. Kal7 knockout animals show exaggerated locomotor responses to psychostimulants and self-administer cocaine more enthusiastically than wildtype mice. Results: To explore the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we infused candidate intracellular interfering peptides to acutely challenge the synaptic function(s) of Kal7 with potential protein binding partners, to determine if plasticity deficits in Kal7-/- mice are the product of developmental processes since conception, or could be produced on a much shorter time scale. We demonstrated that these small intracellular peptides disrupted normal long-term potentiation and long-term depression, strongly suggesting that maintenance of established interactions of Kal7 with PSD-95 and/or GluN2B is crucial to synaptic plasticity. Conclusions: Blockade of the Kal7-GluN2B interaction was most effective at blocking long-term potentiation, but had no effect on long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

Transient Removal of Extracellular Mg2+ Elicits Persistent Suppression of LTP at Hippocampal CA1 Synapses Via PKC Activation

2000 ◽  
Vol 84 (3) ◽  
pp. 1279-1288 ◽  
Author(s):  
Kuei-Sen Hsu ◽  
Wen-Chia Ho ◽  
Chiung-Chun Huang ◽  
Jing-Jane Tsai
Keyword(s):  
Nmda Receptor ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Suppressive Effect ◽  
Dependent Protein Kinase ◽  
Dependent Protein

Previous work has shown that seizure-like activity can disrupt the induction of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecular mechanisms underlying this process better, a set of studies was implemented in area CA1 of rat hippocampal slices using extracellular recording methods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg2+-free artificial cerebrospinal fluid (ACSF) exhibited a persistent suppression of LTP induction. This effect lasted between 2 and 3 h after normal ACSF replacement and was specifically inhibited by N-methyl-d-aspartate (NMDA) receptor antagonistd-2-amino-5-phosphovaleric acid (d-APV) and L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In addition, this suppressive effect was specifically blocked by the selective protein kinase C (PKC) inhibitor NPC-15437. However, neither Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP-dependent protein kinase inhibitor Rp-adenosine 3′,5′-cyclic monophosphothioate (Rp-cAMPS) affected this suppressive effect. This persistent suppression of LTP was not secondary to the long-lasting changes in NMDA receptor activation, because the isolated NMDA receptor–mediated responses did not show a long-term enhancement in response to a 30-min Mg2+-free ACSF application. Additionally, in prior Mg2+-free ACSF–treated slices, the entire frequency-response curve of LTP and long-term depression (LTD) is shifted systematically to favor LTD. These results suggest that the increase of Ca2+ influx through NMDA channels and L-type VOCCs in turn triggering a PKC-dependent signaling cascade is a possible cellular basis underlying this seizure-like activity-induced inhibition of LTP.

scholarly journals GSK3β Modulates Timing-Dependent Long-Term Depression Through Direct Phosphorylation of Kv4.2 Channels

2018 ◽  
Vol 29 (5) ◽  
pp. 1851-1865 ◽  
Author(s):  
Giuseppe Aceto ◽  
Agnese Re ◽  
Andrea Mattera ◽  
Lucia Leone ◽  
Claudia Colussi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Synaptic Strength ◽  
Spike Timing ◽  
Long Term Depression ◽  
Pharmacological Agents ◽  
Type K ◽  
Molecular Determinant ◽  
K Currents

AbstractSpike timing-dependent plasticity (STDP) is a form of activity-dependent remodeling of synaptic strength that underlies memory formation. Despite its key role in dictating learning rules in the brain circuits, the molecular mechanisms mediating STDP are still poorly understood. Here, we show that spike timing-dependent long-term depression (tLTD) and A-type K+ currents are modulated by pharmacological agents affecting the levels of active glycogen-synthase kinase 3 (GSK3) and by GSK3β knockdown in layer 2/3 of the mouse somatosensory cortex. Moreover, the blockade of A-type K+ currents mimics the effects of GSK3 up-regulation on tLTD and occludes further changes in synaptic strength. Pharmacological, immunohistochemical and biochemical experiments revealed that GSK3β influence over tLTD induction is mediated by direct phosphorylation at Ser-616 of the Kv4.2 subunit, a molecular determinant of A-type K+ currents. Collectively, these results identify the functional interaction between GSK3β and Kv4.2 channel as a novel mechanism for tLTD modulation providing exciting insight into the understanding of GSK3β role in synaptic plasticity.

scholarly journals Impairment of cerebellar long-term depression and GABAergic transmission in prion protein deficient mice ectopically expressing PrPLP/Dpl

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yasushi Kishimoto ◽  
Moritoshi Hirono ◽  
Ryuichiro Atarashi ◽  
Suehiro Sakaguchi ◽  
Tohru Yoshioka ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Prion Protein ◽  
Neural Plasticity ◽  
Late Onset ◽  
Eyeblink Conditioning ◽  
Electrophysiological Study ◽  
Synaptic Function ◽  
Long Term Depression ◽  
Underlying Mechanisms

Abstract Prion protein (PrPC) knockout mice, named as the “Ngsk” strain (Ngsk Prnp0/0 mice), show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrPC-like protein (PrPLP/Dpl). Our previous study indicated that the mutant mice also exhibited alterations in cerebellum-dependent delay eyeblink conditioning, even at a young age (16 weeks of age) when neurological changes had not occurred. Thus, this electrophysiological study was designed to examine the synaptic function of the cerebellar cortex in juvenile Ngsk Prnp0/0 mice. We showed that Ngsk Prnp0/0 mice exhibited normal paired-pulse facilitation but impaired long-term depression of excitatory synaptic transmission at synapses between parallel fibres and PCs. GABAA-mediated inhibitory postsynaptic currents recorded from PCs were also weakened in Ngsk Prnp0/0 mice. Furthermore, we confirmed that Ngsk Prnp0/0 mice (7–8-week-old) exhibited abnormalities in delay eyeblink conditioning. Our findings suggest that these alterations in both excitatory and inhibitory synaptic transmission to PCs caused deficits in delay eyeblink conditioning of Ngsk Prnp0/0 mice. Therefore, the Ngsk Prnp0/0 mouse model can contribute to study underlying mechanisms for impairments of synaptic transmission and neural plasticity, and cognitive deficits in the central nervous system.

scholarly journals Long-term depression: a cell biological view

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130138 ◽  
Author(s):  
Morgan Sheng ◽  
Ali Ertürk
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Dendritic Spines ◽  
Crucial Role ◽  
Molecular Mechanisms ◽  
Signalling Pathways ◽  
Long Term Depression ◽  
A Cell ◽  
Biological Programme

Recent studies of the molecular mechanisms of long-term depression (LTD) suggest a crucial role for the signalling pathways of apoptosis (programmed cell death) in the weakening and elimination of synapses and dendritic spines. With this backdrop, we suggest that LTD can be considered as the electrophysiological aspect of a larger cell biological programme of synapse involution, which uses localized apoptotic mechanisms to sculpt synapses and circuits without causing cell death.

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