Synaptotagmins: Beyond Presynaptic Neurotransmitter Release

Synaptotagmins (Syts) are well-established primary Ca2+ sensors to initiate presynaptic neurotransmitter release. They also play critical roles in the docking, priming, and fusion steps of exocytosis, as well as the tightly coupled exo-endocytosis, in presynapses. A recent study by Awasthi and others (2019) shows that Syt3 Ca2+-dependently modulates the postsynaptic receptor endocytosis and thereby promotes the long-term depression (LTD) and the decay of long-term potentiation (LTP). This work highlights the importance of Syt3 in modulating long-term synaptic plasticity and, importantly, extends the function of Syt proteins from presynaptic neurotransmitter release to a new promising postsynaptic receptor internalization.

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

10.21203/rs.3.rs-41613/v1 ◽

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.

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Endocannabinoid dynamics gate spike-timing dependent depression and potentiation

eLife ◽

10.7554/elife.13185 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 24

Author(s):

Yihui Cui ◽

Ilya Prokin ◽

Hao Xu ◽

Bruno Delord ◽

Stephane Genet ◽

...

Keyword(s):

Mathematical Modeling ◽

Synaptic Plasticity ◽

Learning And Memory ◽

Long Term Potentiation ◽

Cellular Mechanism ◽

Spike Timing ◽

Long Term Depression ◽

Term Potentiation ◽

Short And Long Term

Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory.

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Long-Term Potentiation and Long-Term Depression

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.148 ◽

2018 ◽

Cited By ~ 1

Author(s):

Arianna Maffei

Keyword(s):

Synaptic Plasticity ◽

Neural Circuit ◽

Long Term Potentiation ◽

Synaptic Connections ◽

Long Term Depression ◽

Term Potentiation ◽

Functional Implications ◽

The Brain

Synaptic connections in the brain can change their strength in response to patterned activity. This ability of synapses is defined as synaptic plasticity. Long lasting forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), are thought to mediate the storage of information about stimuli or features of stimuli in a neural circuit. Since its discovery in the early 1970s, synaptic plasticity became a central subject of neuroscience, and many studies centered on understanding its mechanisms, as well as its functional implications.

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Persistent memories of long-term potentiation and the N-methyl-d-aspartate receptor

Brain and Neuroscience Advances ◽

10.1177/2398212819848213 ◽

2019 ◽

Vol 3 ◽

pp. 239821281984821 ◽

Cited By ~ 7

Author(s):

TVP Bliss ◽

GL Collingridge

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Brain Disorders ◽

Molecular Pharmacology ◽

Cellular Mechanisms ◽

Long Term Depression ◽

Aspartate Receptor ◽

Term Potentiation ◽

Core Feature

In this article, we describe our involvement in the early days of research into long-term potentiation. We start with a description of the early experiments conducted in Oslo and London where long-term potentiation was first characterised. We discuss the ways in which the molecular pharmacology of glutamate receptors control the induction and expression of long-term potentiation and its counterpart, long-term depression. We then go on to summarise the extraordinary advances in understanding the cellular mechanisms of synaptic plasticity that have taken place in the subsequent half century. Finally, the increasing evidence that impaired long-term potentiation is a core feature of many brain disorders (LToPathies) is addressed by way of a few selected examples.

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Metabotropic glutamate receptors and visual cortical synaptic plasticity

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-186 ◽

1995 ◽

Vol 73 (9) ◽

pp. 1312-1322 ◽

Cited By ~ 13

Author(s):

T. Kamishita ◽

H. Haruta ◽

N. Torii ◽

T. Tsumoto ◽

T. P. Hicks

Keyword(s):

Synaptic Plasticity ◽

Visual Cortex ◽

Metabotropic Glutamate Receptors ◽

Excitatory Amino Acid ◽

Long Term Potentiation ◽

Receptor Subtype ◽

Long Term Depression ◽

Metabotropic Receptor ◽

Term Potentiation

Two forms of use-dependent synaptic plasticity, called long-term potentiation (LTP) and long-term depression (LTD), can be elicited in the visual cortex following different paradigms of electrophysiological stimulation. These neurobiological phenomena often are considered as necessary components of models for the alteration in function of the nervous system that must occur at some level for the establishment and (or) maintenance of memory engrams, for learning processes, or for the consolidation of active neural connections and regression of inactive contacts in the developing brain. It has been postulated that for LTP and LTD to be produced in the hippocampus, activation of a particular subtype of excitatory amino acid receptor, the metabotropic receptor, is a critical requirement. Only recently has it become possible to test this hypothesis directly, as a new compound, (±)-α-methyl-4-carboxyphenylglycine (MCPG), has been introduced and the suggestion made that it selectively antagonizes the metabotropic receptor. This substance has been tested in the present study on responses recorded from slices of rat visual cortex and has been found both to block the activation of the metabotropic receptor and to interfere selectively with the form of synaptic plasticity called LTD. It thus appears from the experiments reported in this paper as though the metabotropic receptor subtype that is blocked by MCPG is required for the expression of LTD but not for the expression of LTP, in the visual cortex of adult rats.Key words: excitatory amino acids, long-term potentiation, long-term depression, visual cortex, (±)-α-methyl-4-carboxyphenylglycine (MCPG).

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

10.1101/2020.12.03.410258 ◽

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.

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Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

Developmental Neuroscience ◽

10.1159/000430435 ◽

2015 ◽

Vol 37 (3) ◽

pp. 263-272 ◽

Cited By ~ 4

Author(s):

Giulia Zanni ◽

Kai Zhou ◽

Ilse Riebe ◽

Cuicui Xie ◽

Changlian Zhu ◽

...

Keyword(s):

Synaptic Plasticity ◽

Young Patients ◽

Long Term Potentiation ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

High Frequency Stimulation ◽

Excitatory Postsynaptic Potential ◽

Long Term Depression ◽

Term Potentiation

Radiotherapy is common in the treatment of brain tumors in children but often causes deleterious, late-appearing sequelae, including cognitive decline. This is thought to be caused, at least partly, by the suppression of hippocampal neurogenesis. However, the changes in neuronal network properties in the dentate gyrus (DG) following the irradiation of the young, growing brain are still poorly understood. We characterized the long-lasting effects of irradiation on the electrophysiological properties of the DG after a single dose of 6-Gy whole-brain irradiation on postnatal day 11 in male Wistar rats. The assessment of the basal excitatory transmission in the medial perforant pathway (MPP) by an examination of the field excitatory postsynaptic potential/volley ratio showed an increase of the synaptic efficacy per axon in irradiated animals compared to sham controls. The paired-pulse ratio at the MPP granule cell synapses was not affected by irradiation, suggesting that the release probability of neurotransmitters was not altered. Surprisingly, the induction of long-term synaptic plasticity in the DG by applying 4 trains of high-frequency stimulation provoked a shift from long-term potentiation (LTP) to long-term depression (LTD) in irradiated animals compared to sham controls. The morphological changes consisted in a virtually complete ablation of neurogenesis following irradiation, as judged by doublecortin immunostaining, while the inhibitory network of parvalbumin interneurons was intact. These data suggest that the irradiation of the juvenile brain caused permanent changes in synaptic plasticity that would seem consistent with an impairment of declarative learning. Unlike in our previous study in mice, lithium treatment did unfortunately not ameliorate any of the studied parameters. For the first time, we show that the effects of cranial irradiation on long-term synaptic plasticity is different in the juvenile compared with the adult brain, such that while irradiation of the adult brain will only cause a reduction in LTP, irradiation of the juvenile brain goes further and causes LTD. Although the mechanisms underlying the synaptic alterations need to be elucidated, these findings provide a better understanding of the effects of irradiation in the developing brain and the cognitive deficits observed in young patients who have been subjected to cranial radiotherapy.

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Coexistence of Muscarinic Long-Term Depression With Electrically Induced Long-Term Potentiation and Depression at CA3–CA1 Synapses

Journal of Neurophysiology ◽

10.1152/jn.00144.2006 ◽

2006 ◽

Vol 96 (6) ◽

pp. 3114-3121 ◽

Cited By ~ 19

Author(s):

Eve McCutchen ◽

Cary L. Scheiderer ◽

Lynn E. Dobrunz ◽

Lori L. McMahon

Keyword(s):

Synaptic Plasticity ◽

Low Frequency ◽

Long Term Potentiation ◽

Receptor Activation ◽

High Frequency Stimulation ◽

Muscarinic Agonist ◽

Long Term Depression ◽

Term Potentiation ◽

Frequency Stimulation

Our laboratory recently characterized a form of long-term depression (LTD) at CA3–CA1 synapses mediated by M1 muscarinic receptors (mAChRs), termed muscarinic LTD (mLTD). mLTD is both activity and NMDAR dependent, characteristics shared by forms of synaptic plasticity thought to be relevant to learning and memory, including long-term potentiation (LTP) induced by high-frequency stimulation (HFS-LTP) and long-term depression induced by low-frequency stimulation (LFS-LTD). However, it remains unclear whether mLTD can occur sequentially with these electrically induced forms of hippocampal plasticity or whether mLTD might interact with them. The first goal of this study was to examine the interplay of mLTD and HFS-LTP. We report that mLTD expression does not alter subsequent induction of HFS-LTP and, further, at synapses expressing HFS-LTP, mLTD can mediate a novel form of depotentiation. The second goal was to determine whether mLTD would alter LFS-LTD induction and/or expression. Although we show that mLTD is occluded by saturation of LFS-LTD, suggesting mechanistic similarity between these two plasticities, saturation of mLTD does not occlude LFS-LTD. Surprisingly, however, the LFS-LTD that follows cholinergic receptor activation is NMDAR independent, indicating that application of muscarinic agonist induces a change in the induction mechanism required for LFS-LTD. These data demonstrate that mLTD can coexist with electrically induced forms of synaptic plasticity and support the hypothesis that mLTD is one of the mechanisms by which the cholinergic system modulates hippocampal function.

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Syndapin I Loss-of-Function in Mice Leads to Schizophrenia-Like Symptoms

Cerebral Cortex ◽

10.1093/cercor/bhaa013 ◽

2020 ◽

Vol 30 (8) ◽

pp. 4306-4324 ◽

Cited By ~ 1

Author(s):

Nicole Koch ◽

Dennis Koch ◽

Sarah Krueger ◽

Jessica Tröger ◽

Victor Sabanov ◽

...

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Synaptic Activity ◽

Actin Dynamics ◽

Loss Of Function ◽

Cellular Mechanisms ◽

Long Term Depression ◽

Membrane Recruitment ◽

Term Potentiation

Abstract Schizophrenia is associated with cognitive and behavioral dysfunctions thought to reflect imbalances in neurotransmission systems. Recent screenings suggested that lack of (functional) syndapin I (PACSIN1) may be linked to schizophrenia. We therefore studied syndapin I KO mice to address the suggested causal relationship to schizophrenia and to analyze associated molecular, cellular, and neurophysiological defects. Syndapin I knockout (KO) mice developed schizophrenia-related behaviors, such as hyperactivity, reduced anxiety, reduced response to social novelty, and an exaggerated novel object response and exhibited defects in dendritic arborization in the cortex. Neuromorphogenic deficits were also observed for a schizophrenia-associated syndapin I mutant in cultured neurons and coincided with a lack of syndapin I–mediated membrane recruitment of cytoskeletal effectors. Syndapin I KO furthermore caused glutamatergic hypofunctions. Syndapin I regulated both AMPAR and NMDAR availabilities at synapses during basal synaptic activity and during synaptic plasticity—particularly striking were a complete lack of long-term potentiation and defects in long-term depression in syndapin I KO mice. These synaptic plasticity defects coincided with alterations of postsynaptic actin dynamics, synaptic GluA1 clustering, and GluA1 mobility. Both GluA1 and GluA2 were not appropriately internalized. Summarized, syndapin I KO led to schizophrenia-like behavior, and our analyses uncovered associated molecular and cellular mechanisms.

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