scholarly journals Dissecting the Roles of Kalirin-7/PSD95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2019 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R. Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard E. Mains
Keyword(s):  
Synaptic Plasticity ◽  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Postsynaptic Density ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Multiple Components ◽  
Term Potentiation ◽  
Knockout Animals

AbstractKalirin-7 (Kal7) is a Rac1/RhoG GEF and multidomain scaffold localized to the postsynaptic density which plays an important role in synaptic plasticity. Behavioral and physiological phenotypes observed in the Kal7 knockout mouse are quite specific: genetics of breeding, growth, strength and coordination are normal; Kal7 knockout animals self-administer cocaine far more than normal mice, show exaggerated locomotor responses to cocaine, but lack changes in dendritic spine morphology seen in wildtype mice; Kal7 knockout mice have depressed surface expression of GluN2B receptor subunits and exhibit marked suppression of long-term potentiation and depression in hippocampus, cerebral cortex, and spinal cord; and Kal7 knockout mice have dramatically blunted perception of pain. To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we administered intracellular blocking peptides to acutely change Kal7 function at the synapse, to determine if plasticity deficits in Kal7-/-mice are the product of developmental processes since conception, or could be detected on a much shorter time scale. We found that specific disruption of the interactions of Kal7 with PSD-95 or GluN2B resulted in significant suppression of long-term potentiation and long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.Graphical Table of ContentsThe postsynaptic density is an integral player in receiving, interpreting and storing signals transmitted by presynaptic terminals. The correct molecular composition is crucial for successful expression of synaptic plasticity. Key components of the postsynaptic density include ligand-gated ion channels, structural and binding proteins, and multidomain scaffolding plus enzymatic proteins. These studies address whether the multiple components of the synaptic density bind together in a static or slowly adapting molecular complex, or whether critical interactions are fluid on a minute-to-minute basis.

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 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.

scholarly journals Chronic neuronal excitation leads to homeostatic suppression of structural long-term potentiation

2021 ◽  
Author(s):  
Hiromi H Ueda ◽  
Aiko Sato ◽  
Maki Onda ◽  
Hideji Murakoshi
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Homeostatic Plasticity ◽  
Ca1 Neurons ◽  
Downstream Signaling ◽  
Neuronal Excitation ◽  
Term Potentiation ◽  
Hippocampal Ca1

Synaptic plasticity is long-lasting changes in synaptic currents and structure. When neurons are exposed to signals that induce aberrant neuronal excitation, they increase the threshold for the induction of synaptic plasticity, called homeostatic plasticity. To further understand the homeostatic regulation of synaptic plasticity and its molecular mechanisms, we investigated glutamate uncaging/photoactivatable (pa)CaMKII-dependent sLTP induction in hippocampal CA1 neurons after chronic neuronal excitation by GABAA receptor antagonists. The neuronal excitation suppressed the glutamate uncaging-evoked Ca2+ influx and failed to induce sLTP. Single-spine optogenetic stimulation using paCaMKII also failed to induce sLTP, suggesting that CaMKII downstream signaling is impaired in response to chronic neuronal excitation. Furthermore, while the inhibition of Ca2+ influx was protein synthesis-independent, paCaMKII-induced sLTP depended on it. Our findings demonstrate that chronic neuronal excitation suppresses sLTP in two independent ways (i.e., the inhibitions of Ca2+ influx and CaMKII downstream signaling), which may contribute to the robust neuronal protection in excitable environments.

scholarly journals Phosphorylation of AMPA receptor subunit GluA1 regulates clathrin-mediated receptor endocytosis

2020 ◽  
Author(s):  
Matheus F. Sathler ◽  
Latika Khatri ◽  
Jessica P. Roberts ◽  
Regina C.C. Kubrusly ◽  
Edward B. Ziff ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Synaptic Strength ◽  
Coated Pits ◽  
Receptor Endocytosis ◽  
Term Potentiation ◽  
Exact Function ◽  
Up Scaling

AbstractSynaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. In particular, during long-term potentiation and synaptic up-scaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to activity-dependent phosphorylation of AMPAR subunit GluA1, and subsequent increases in GluA1 surface expression, which can be achieved by either an increase in exocytosis or a decrease in endocytosis of the receptors. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we first employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 Serine 845 (S845) plays a more important role in receptor endocytosis than exocytosis during synaptic plasticity. Notably, endocytosis of AMPARs depends upon the clathrin adaptor, AP2, which recruits cargo proteins into endocytic clathrin coated pits. Importantly, the KRMK (Lysine-Arginine-Methionine-Lysine) motif in the carboxyl-terminus of GluA1 is suggested to be an AP2 binding site, but the exact function has not been defined. Moreover, the GluA1 KRMK motif is closely located to one of GluA1 phosphorylation sites, serine 845 (S845), and GluA1 S845 dephosphorylation is suggested to enhance endocytosis during long-term depression. In fact, we show that an increase in GluA1 S845 phosphorylation by two distinct forms of synaptic plasticity, long-term potentiation and synaptic up-scaling, diminishes the binding of the AP2 adaptor. This reduces endocytosis, resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated endocytosis of AMPARs.

scholarly journals In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus

2003 ◽  
Vol 358 (1432) ◽  
pp. 757-763 ◽  
Author(s):  
Christopher Pittenger ◽  
Eric R. Kandel
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Mammalian Brain ◽  
Marine Snail ◽  
Synaptic Facilitation ◽  
Term Potentiation ◽  
Two Systems ◽  
Mechanisms Of Plasticity

Long-term synaptic plasticity is thought to underlie many forms of long-lasting memory. Long-lasting plasticity has been most extensively studied in the marine snail Aplysia and in the mammalian hippocampus, where Bliss and Lømo first described long-term potentiation 30 years ago. The molecular mechanisms of plasticity in these two systems have proven to have many similarities. Here, we briefly describe some of these areas of overlap. We then summarize recent advances in our understanding of the mechanisms of long-lasting synaptic facilitation in Aplysia and suggest that these may prove fruitful areas for future investigation in the mammalian hippocampus and at other synapses in the mammalian brain.

scholarly journals NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130131 ◽  
Author(s):  
Pojeong Park ◽  
Arturas Volianskis ◽  
Thomas M. Sanderson ◽  
Zuner A. Bortolotto ◽  
David E. Jane ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Recent Work ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Extensive Literature ◽  
Synaptic Activation ◽  
Aspartate Receptor ◽  
Term Potentiation

N -methyl- d -aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.

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 Long-Term Potentiation Induces Extrasynaptic Exocytosis of Glun2A-containing NMDA Receptors that is Mainly Controlled by SNAP23

2019 ◽  
Author(s):  
Xiaojun Yu ◽  
Wei Li ◽  
Tong Wang
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptors ◽  
Postsynaptic Density ◽  
Super Resolution ◽  
Time Lapse ◽  
Long Term Potentiation ◽  
Live Imaging ◽  
Term Potentiation ◽  
Specific Regulation

AbstractNMDA receptors (NMDAR) are key players in the initiation of synaptic plasticity that underlies learning and memory. Long-term potentiation (LTP) of synapses require an increased calcium current via NMDA channels to trigger modifications in postsynaptic density (PSD). It is generally believed that the amount of NMDARs on the postsynaptic surface remains stationary, whereas their subunit composition is dynamically fluctuated during this plasticity process. However, the molecular machinery underlying this subunit-specific regulation remains largely elusive. Here, by detecting the time-lapse changes of surface GluN2A and GluN2B subunit levels using biochemical approaches, surface immunostaining, live-imaging and super-resolution microscopy, we uncovered a transient increase of surface GluN2A-type NMDARs shortly after the induction of chemical long term potentiation (cLTP). These augmented sub-diffraction-limited GluN2A clusters predominantly exist in extrasynaptic domains. We also showed that the spine-enriched SNARE associated protein SNAP-23, and to a minor extent its homologue SNAP-25, control both the basal and regulated surface level of GluN2A receptors. Using a total internal reflection fluorescence microscopy (TIRFM) based live-imaging assay, we resolved and analyzed individual exocytic events of NMDARs in live neurons and found that cLTP raised the frequency of NMDAR exocytosis at extrasynaptic regions, without altering the duration or the package size of these events. Our study thereby provides direct evidence that synaptic plasticity controls the postsynaptic exocytosis machinery, which induces the insertion of more GluN2A receptors into the extrasynaptic area.Significance StatementMemory formation involves the long-term modification of synapses, which is called synaptic plasticity. In the postsynaptic density (PSD) of excited neurons, this modification process occurs on a minute timescale, initiated by the opening of NMDARs that trigger downstream cascades to fix the potentiation (LTP) at specific synapses for longer timescales. Here, using a novel live-imaging assay we resolved the dynamic delivery of NMDARs to the cell surface, and found that only the insertion frequency, not the duration of individual insertion or number of GluN2A subunits each of these NMDAR vesicles contains, was altered during the synaptic potentiation process. We also identified SNAP-23 as the key molecule mediating this activity dependent NMDAR surface delivery. This study provides a novel mechanism of how NMDARs are regulated in the short window to initiate the long-lasting synaptic modifications.

Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 354-360 ◽  
Author(s):  
Yu-Xing Ge ◽  
Ying-Ying Lin ◽  
Qian-Qian Bi ◽  
Yu-Juan Chen
Keyword(s):  
Synaptic Plasticity ◽  
Temporal Lobe Epilepsy ◽  
Synaptic Vesicle ◽  
Long Term Potentiation ◽  
Synaptic Dysfunction ◽  
Over Expression ◽  
Term Potentiation ◽  
Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

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